Antimicrobial Compounds And Methods Of Making And Using The Same

ABSTRACT

The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and/or reducing the risk of microbial infections in humans and animals.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/681,806, filed Apr. 8, 2015, which is a continuation of U.S.application Ser. No. 13/501,836, filed Apr. 13, 2012, which is anational stage application, filed under 35 U.S.C. §371 of InternationalApplication No. PCT/US2010/052924, filed Oct. 15, 2010, which claimspriority to and the benefit of U.S. Provisional Patent Application No.61/252,478, filed Oct. 16, 2009; U.S. Provisional Patent Application No.61/314,287 filed Mar. 16, 2010; and U.S. Provisional Patent ApplicationNo. 61/358,201, filed Jun. 24, 2010, the contents of each of which arehereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to the field of antimicrobialcompounds and to methods of making and using them. These compounds areuseful for treating, preventing, and reducing the risk of microbialinfections in humans and animals.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once thought that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such views have been challengedbecause strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. Almost every antibioticagent developed for clinical use has ultimately encountered problemswith the emergence of resistant bacteria. For example, resistant strainsof Gram-positive bacteria such as methicillin-resistant staphylococci,penicillin-resistant streptococci, and vancomycin-resistant enterococcihave developed. Resistant bacteria can cause serious and even fatalresults for infected patients. See, e.g., Lowry, F. D. “AntimicrobialResistance: The Example of Staphylococcus aureus,” J. Clin. Invest.,vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, H. S. and Moellering,R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J. Med., vol. 335,pp. 1445-53 (1996).

The discovery and development of new antibacterial agents has been fordecades a major focus in many pharmaceutical companies. Nonetheless, inmore recent years there has been an exodus of pharmaceutical companiesfrom this area of research and drug development. As a consequence ofthis exodus, there have been very few new antibiotics entering themarket. This lack of new antibiotics is particularly disturbing,especially at a time when bacterial resistance to current therapies isincreasing both in the hospital and community settings.

In the search for new antibiotic agents, researchers have triedcombining or linking various portions of antibiotic molecules to createmultifunctional or hybrid compounds Other researchers have tried makingderivatives of known classes of antibiotics, e.g., telithromycin, whichis sold under the trade name Ketek®, is a derivative of erythromycin.However, these approaches have met with limited success.

An approach to developing new antimicrobial compounds is to designmodulators, for example, inhibitors, of bacterial ribosome function. Bymodulating or inhibiting bacterial ribosome function such antimicrobialcompounds could interfere with essential processes such as RNAtranslation and protein synthesis, thereby providing an antimicrobialeffect. In fact, some antibiotic compounds such as erythromycin,clindamycin, and linezolid are known to bind to the ribosome.

The present invention utilizes a structure based drug design approachfor discovering and developing new antimicrobial agents. This approachstarts with the high resolution X-ray crystal of the ribosome to designnew classes of antimicrobial compounds having specific chemicalstructures, ribosome binding characteristics, and antimicrobialactivity. This structure based drug discovery approach is described inthe following publication: Franceschi, F. and Duffy, E. M.,“Structure-based drug design meets the ribosome”, BiochemicalPharmacology, vol. 71, pp. 1016-1025 (2006).

Based on this structure based drug design approach, the presentinvention describes new chemical classes of antimicrobial compoundsuseful for treating bacterial infections in humans and animals. Withoutbeing limited by theories, these compounds are believed to inhibitbacterial ribosome function by binding to the ribosome. By takingadvantage of these ribosome binding sites, the antimicrobial compoundsof the present invention can provide better activity, especially againstresistant strains of bacteria, than current antibiotic compounds.

The present invention utilizes a structure based drug design approachfor discovering and developing new antimicrobial agents. This approachstarts with the high resolution X-ray crystal of the ribosome to designnew classes of antimicrobial compounds having specific chemicalstructures, ribosome binding characteristics, and desired antimicrobialactivity. This structure based drug discovery approach is described inthe following publication: Franceschi, F. and Duffy, E. M.,“Structure-based drug design meets the ribosome”, BiochemicalPharmacology, vol. 71, pp. 1016-1025 (2006).

The present invention therefore fills an important ongoing need forproviding new antimicrobial agents, particularly for antimicrobialagents, having activity against resistant pathogenic bacterialorganisms.

SUMMARY OF THE INVENTION

The present invention relates generally to the field of antimicrobialcompounds and to methods of making and using them. These compounds areuseful for treating, preventing, and reducing the risk of microbialinfections in humans and animals. The present invention also providespharmaceutically acceptable salts, esters, N-oxides, and prodrugs ofthese compounds.

The present invention provides compounds having the structure

wherein

is a chemical moiety selected from:

wherein U is selected from the group consisting of CR³R³, O, NR⁴, orS(O)_(n), C═O, C═NOR³, alternatively, two R³s are taken together to forma carbonyl,V is independently selected from —CR^(4a)— or —N—;wherein

represents a fused 5 to 7 member saturated, unsaturated, or aromaticcarbocyclic or heterocyclic ring system;W is O, NR¹, NOR¹, or S, alternatively W═ is selected from thecombination of HO— and H— both attached to the same carbon atom or thecombination of (C₁₋₈ alkyl)O— and H— both attached to the same carbonatom;

represents a single bond or a double bond such that when

is a single bond, X is selected from O, NR², and S(O)_(n) and Y is C—R³,and when

is a double bond, X is N and Y is a carbon atom,Z is selected from the group consisting of O, NR⁴, or S(O)_(n),R¹ is selected from H and C₁₋₈ alkyl,R² is selected from H and C₁₋₈ alkyl,R^(4a) is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,R^(4a) is selected from H and C₁₋₈ alkyl,n is 0, 1, or 2,alternatively, -G-H-J is selected from:

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b), wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;wherein n is 0, 1, or 2;alternatively, -G-H-J is selected from

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isa C or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;C-B-A-, -D-E-F, and -G-H-J are chemical moieties, whereinA, D and G are independently selected from the group consisting of:

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   (e) —O—, (f) —NR⁶—, (g) —S(O)_(p)—, (h) —C(O)—, (i) —C(O)O—, (j)        —OC(O)—, k) —OC(O)O—, (l) —C(O)NR⁶—, (m) —NR⁶CO—, (n)        —NR⁶C(O)NR⁶—; (o) —C(═NR⁶)—, (p) —C(═NR⁶)O—, (q) —OC(═NR⁶)—, (r)        —C(═NR⁶)NR⁶—, (s) —NR⁶C(═NR⁶)—, (t) —C(═S)—, (u) —C(═S)NR⁶—, (v)        —NR⁶C(═S)—, (w) —C(O)S—, (x) —SC(O)—, (y) —OC(═S)—, (z)        —C(═S)O—, (aa) —NR⁶(CNR⁶)NR⁶—, (bb) —CR⁶R⁶C(O)—, (cc)        —C(O)NR⁶(CR⁶R⁶)_(t)—, (dd) a 3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur,    -   (ee) a 3-14 member saturated, unsaturated, or aromatic        carbocycle, and    -   (f) —(CR⁶R⁶)_(r)—        wherein (dd) or (ee) is optionally substituted with one or more        R⁵ groups;        B, E, and H are independently selected from the group consisting        of:    -   (a) a single bond,    -   (b) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,    -   (c) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,        wherein (b) or (c) is optionally substituted with one or more R⁵        groups;    -   (d) —(C₁₋₈ alkyl)-, (e) —(C₂₋₈ alkenyl)-, (f) —(C₂₋₈ alkynyl)-,        wherein        -   i) 0-4 carbon atoms in any of (d)-(f) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (d)-(f) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (d)-(f) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;            and (g) —(CR⁶R⁶)_(t)—,            C, F, and J are independently selected from the group            consisting of:    -   (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h)        —CN, (i) —N₃ (j) —NO₂, (k) —NR⁶(CR⁶R⁶)_(t)R⁸, (l) —OR⁸, (m)        —S(O)_(p)(CR⁶R⁶)_(t)R⁸, (n) —C(O)(CR⁶R⁶)_(t)R⁸, (o)        —OC(O)(CR⁶R⁶)_(t)R⁸, (p) —SC(O)(CR⁶R⁶)_(t)R⁸, (q)        —C(O)O(CR⁶R⁶)_(t)R⁸, (r) —NR⁶C(O)(CR⁶R⁶)_(t)R⁸, (s)        —C(O)NR⁶(CR⁶R⁶)_(t)R⁶, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁸, (u)        —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁸, (v) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁸, (w)        —C(═NOR⁹)(CR⁶R⁶)_(t)R⁸, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁸, (y)        —OC(O)NR⁶(CR⁶R⁶)_(t)R*, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (aa)        —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁸, (bb) —S(O)_(p)NR(CR⁶R⁶)R⁸, (cc)        —NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (dd) —NR⁶R⁸, (ee)        —NR⁶(CR⁶R⁶)_(t)R⁸, (ff) —OH, (gg) —NR⁸R⁸, (hh) —OCH₃, (ii)        —S(O)_(p)R⁸, (jj) —NC(O)R⁸, (kk) —NR⁶C(NR⁶)NR⁶R⁸, (ll) a C₁₋₈        alkyl group, (mm) a C₂₋₈ alkenyl group, (nn) a C₂₋₈alkynyl        group, (oo) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, (pp) a 3-14        member saturated, unsaturated, or aromatic carbocycle, (qq)        —(CR⁶R⁶)_(t)NR⁶(CR⁶R⁶)_(t)R⁸, (rr)        —N[(CR⁶R⁶)_(t)R⁸][C═O(CR⁶R⁶)_(t)R⁸], (ss)        —(CR⁶R⁶)_(t)N[(CR⁶R⁶)_(t)R⁸][(CR⁶R⁶)_(t)R⁸], (tt)        —(CR⁶R⁶)_(t)NR⁶(C═O)(CR⁶R⁶)_(t)R⁸, (uu) - haloalkyl, (vv)        —C(O)(CR⁶)[(CR⁶R⁶)_(t)R⁸]R⁸, (ww) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (xx)        —(CR⁶R⁶)_(t)C(O)O(CR⁶R⁶)_(t)R⁸, (yy) —NR⁶C(O)CR⁸R⁸R⁸, (zz)        —N[(CR⁶R⁶)_(t)R⁸]C(O)R⁸, and (aaa) —S(O)_(p)NR⁸R⁸,        wherein (ll) through (pp) is optionally substituted with one or        more R⁷ groups,        R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e)        I, (f) —CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k)        —OR⁸, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈        alkenyl, (o) —C₁₋₈ alkynyl, (p) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic carbocycle), (r)        -haloalkyl, (s) —SR⁶, (t) -3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic        carbocycle; alternatively, two R⁵ groups are taken together to        form a carbocycle;

wherein (m) through (r) and (t) through (u) is optionally substitutedwith one or more R_(x);

R⁶ is selected from (a) hydrogen, (b) —C₁₋₈ alkyl or alternatively twoR⁶ groups are taken together to form a carbocycle, (c) -haloalkyl, (d)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and (e) -3-14 member saturated, unsaturated, oraromatic carbocycle;wherein (b) through (e) is optionally substituted with one or more R⁸;R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (l)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (l) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶. (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl,(s) —NR⁶R⁸, (t) —OR⁸, (u) —(CR⁶R⁶)_(t)NR⁶R⁸, (v) —CR⁶R⁸R⁸, (w) —SR⁶, (x)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or aromaticcarbocycle, (z) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (aa) —S(O)_(p)R⁸, (bb)—NR⁶C(O)NR⁶R⁶, (cc) —NR⁶C(O)R⁶, and (dd) —C(═NR⁶)NR⁶R⁶;

wherein (m) through (q) and (x) through (y) are optionally substitutedwith one or more R^(9′);

R⁸ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (l)—CF₃, (g) —CN, (h) —Ni (i) —NO₂, (j) —NR⁶R⁹, (k) —OR⁸, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, (s) -3-14 member saturated, unsaturated, or aromatic carbocycle,(t) -haloalkyl, (u) —C(O)(CR⁶R⁶)_(t)R⁹, (v) —SR⁶, (w)—OC(O)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)NR⁶R⁹, (y) —NR⁶C(O)R⁹, (z)—NR⁶(CNR⁹)(NR⁶R⁶), (aa) —ONR⁶(CNR⁶)NR⁶R⁶, (bb) —C(═NR⁹)NR⁶R⁶, (cc)—S(O)_(p)R⁹, (dd) —(CR⁶R⁶)_(t)C(O)NR⁶R⁹, (ee) —(CR⁶R⁶)_(t)OR⁹, and (ff)—(CR⁶R⁶)_(t)NR⁶R⁹;

wherein (m) through (s) is optionally substituted with one or more R⁹;

R⁹ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R¹⁰, (k) —OR⁸, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)_(t)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)OR⁶, (u) —O(CR⁶R⁶)NR⁶R¹⁰, (v) —C(O)R⁶, (w) —SR⁶, (x) —C(O)OR¹⁰,(y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated,or aromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur), (aa) —(C₁₋₈alkyl)-(3-14 member saturated, unsaturated, or aromatic carbocycle),(bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶, (ee)—NR⁶C(O)NR⁶R⁶, (f) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R¹⁰;

wherein (n) through (r) and (z) through (aa) is optionally substitutedwith one or more R¹⁰;

R¹⁰ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (l)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)_(t)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R⁶, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR⁶, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁶, (ff) —O(CR⁶R⁶)_(t)OR⁸, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R⁶;

optionally, wherein either the group -D-E-F or the group -G-H-J isabsent (e.g., the group D-E-F or the group -G-H-J represents hydrogen),but both -D-E-F and -G-H-J are not simultaneously absent;

p is 0, 1, or 2, andt is 0, 1, 2, or 3,or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In addition, the invention provides methods of synthesizing theforegoing compounds. Following synthesis, a therapeutically effectiveamount of one or more of the compounds can be formulated with apharmaceutically acceptable carrier for administration to a human oranimal for use as antimicrobial agents, particularly as antibacterialagents. In certain embodiments, the compounds of the present inventionare useful for treating, preventing, or reducing the risk of microbialinfections or for the manufacture of a medicament for treating,preventing, or reducing the risk of microbial infections. Accordingly,the compounds or the formulations can be administered, for example, viaoral, parenteral, otic, ophthalmic, nasal, or topical routes, to providean effective amount of the compound to the human or animal.

The foregoing and other aspects and embodiments of the invention can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used asantimicrobial agents, more particularly as antibacterial agents.

The present invention includes pharmaceutically acceptable salts,esters, tautomers, N-oxides, and prodrugs thereof.

The compounds described herein can have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom canbe isolated in optically active or racemic forms. It is well known inthe an how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and can be isolated as a mixture of isomers or as separateisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless specificstereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention. Furthermore, theinvention also includes metabolites of the compounds described herein.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R⁶moieties, then R⁶ at each occurrence is selected independently from thedefinition of R⁶. Also, combinations of substituents and/or variablesare permissible, but only if such combinations result in stablecompounds within a designated atom's normal valency.

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms in the compounds of thepresent invention, these, where appropriate, can be converted toN-oxides by treatment with an oxidizing agent (e.g., MCPBA and/orhydrogen peroxides). Thus, shown and claimed nitrogen atoms areconsidered to cover both the shown nitrogen and its N-oxide (N→O)derivative, as appropriate.

One approach to developing improved anti-proliferative andanti-infective agents is to provide modulators (for example, inhibitors)of ribosome function.

Ribosomes are ribonucleoproteins, which are present in both prokaryotesand eukaryotes. Ribosomes are the cellular organelles responsible forprotein synthesis. During gene expression, ribosomes translate thegenetic information encoded in a messenger RNA into protein (Garrett etal. (2000) “The Ribosome: Structure, Function, Antibiotics and CellularInteractions,” American Society for Microbiology, Washington, D.C.).

Ribosomes comprise two nonequivalent ribonucleoprotein subunits. Thelarger subunit (also known as the “large ribosomal subunit”) is abouttwice the size of the smaller subunit (also known as the “smallribosomal subunit”). The small ribosomal subunit binds messenger RNA(mRNA) and mediates the interactions between mRNA and transfer RNA(tRNA) anticodons on which the fidelity of translation depends. Thelarge ribosomal subunit catalyzes peptide bond formation, i.e. thepeptidyl-transferase reaction of protein synthesis, and includes, atleast, three different tRNA binding sites known as the aminoacyl,peptidyl, and exit sites. The aminoacyl site or A-site accommodates theincoming aminoacyl-tRNA that is to contribute its amino acid to thegrowing peptide chain. Also, the A space of the A-site is important. Thepeptidyl site or P-site accommodates the peptidyl-tRNA complex, i.e.,the tRNA with its amino acid that is part of the growing peptide chain.The exit or E-site accommodates the deacylated tRNA after it has donatedits amino acid to the growing polypeptide chain.

1. DEFINITIONS

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with at least one chiral center. It hastwo enantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n-1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem.Educ. 1964, 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Further, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques, ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomers” refers to compounds whose structures differ markedly inarrangement of atoms, but which exist in easy and rapid equilibrium. Itis to be understood that compounds of the present invention may bedepicted as different tautomers. It should also be understood that whencompounds have tautomeric forms, all tautomeric forms are intended to bewithin the scope of the invention, and the naming of the compounds doesnot exclude any tautomer form.

Some compounds of the present invention can exist in a tautomeric formwhich are also intended to be encompassed within the scope of thepresent invention.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds

A tautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers can be reached. The exact ratio of the tautomers dependson several factors, including temperature, solvent, and pH. The conceptof tautomers that are interconvertable by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism, is exhibited by glucose.It arises as a result of the aldehyde group (—CHO) in a sugar chainmolecule reacting with one of the hydroxy groups (—OH) in the samemolecule to give it a cyclic (ring-shaped) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formationof a delocalized anion (e.g. an enolate); 3. protonation at a differentposition of the anion; Acid: 1. protonation; 2. formation of adelocalized cation; 3. deprotonation at a different position adjacent tothe cation.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g. in thenucleobases guanine, thymine, and cytosine), amine-enamine andenamine-enamine. An example below is included for illustrative purposes,and the present invention is not limited to this example:

The terms “crystal polymorphs” or “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or salt or solvate thereof) cancrystallize in different crystal packing arrangements, all of which havethe same elemental composition. Different crystal forms usually havedifferent X-ray diffraction patterns, infrared spectral, melting points,density hardness, crystal shape, optical and electrical properties,stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom, usually a carbon, oxygen, or nitrogenatom, is replaced with a selection from the indicated group, providedthat the designated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., ═O), then 2 hydrogens on the atom are replaced. Ring doublebonds, as used herein, are double bonds that are formed between twoadjacent ring atoms (e.g., C═C, C═N, N═N, etc.).

As used herein, the term “anomeric carbon” means the acetal carbon of aglycoside.

As used herein, the term “glycoside” is a cyclic acetal.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Some examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, andn-octyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. For example C₂₋₆ alkenyl is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkenyl groups.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more triplecarbon-carbon bonds that can occur in any stable point along the chain,such as ethynyl and propynyl. For example, C₂₋₆ alkynyl is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkynyl groups.

Furthermore, “alkyl”, “alkenyl”, and “alkynyl” are intended to includemoieties which are diradicals, i.e., having two points of attachment, anexample of which in the present invention is when D is selected fromthese chemical groups. A nonlimiting example of such an alkyl moietythat is a diradical is —CH₂CH₂—, i.e., a C₂ alkyl group that iscovalently bonded via each terminal carbon atom to the remainder of themolecule. The alkyl diradicals are also known as “alkylenyl” radicals.The alkenyl diradicals are also known as “alkenylenyl” radicals. Thealkynyl diradicals are also known as “alkynylenyl” radicals.

As used herein, “cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₈ cycloalkylis intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

As used herein “counterion” is used to mean a positively or negativelycharged species present in conjunction with an ion of opposite charge. Anonlimiting example of a counterion is an ion or ions present tocounterbalance the charge or charges on an organic compound. Nonlimitingexamples of counterions include chloride, bromide, hydroxide, acetate,sulfate, and ammonium.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo substituents.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) wherein v=1 to 3 and w=1 to (2v+1)). Examplesof haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein, “alkoxy” refers to an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxygroups. C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,and C₈ alkoxy groups. Examples of alkoxy include, but are not limitedto, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “alkylthio” refers to an alkyl group as defined abovewith the indicated number of carbon atoms attached through a sulfurbridge. C₁₋₆ alkylthio, is intended to include C₁, C₂, C₃, C₄, C₅, andC₆ alkylthio groups. C₁₋₆ alkylthio, is intended to include C₁, C₂, C₃,C₄, C₅, C₆, C₇, and C₈ alkylthio groups.

As used herein, “carbocycle” or “carbocyclic ring” is intended to mean,unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or12-membered monocyclic, bicyclic or tricyclic ring, any of which can besaturated, unsaturated (including partially and fully unsaturated), oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.As shown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when oneor more carbon atoms link two non-adjacent carbon atoms. Preferredbridges are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring can also be present onthe bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spirorings are also included.

As used herein, the term “heterocycle” means, unless otherwise stated, astable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclicor tricyclic ring which is saturated, unsaturated (including partiallyand fully unsaturated), or aromatic, and consists of carbon atoms andone or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur,and including any bicyclic or tricyclic group in which any of theabove-defined heterocyclic rings is fused or attached to a second ring(e.g., a benzene ring). The nitrogen and sulfur heteroatoms canoptionally be oxidized (i.e., N→O and S(O)_(p), wherein p=1 or 2). Whena nitrogen atom is included in the ring it is either N or NH, dependingon whether or not it is attached to a double bond in the ring (i.e., ahydrogen is present if needed to maintain the tri-valency of thenitrogen atom). The nitrogen atom can be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, as defined). Theheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein can be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclecan optionally be quaternized. Bridged rings are also included in thedefinition of heterocycle. A bridged ring occurs when one or more atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Preferred bridges include, but are not limited to, one carbon atom, twocarbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. When a ring is bridged, the substituents recitedfor the ring can also be present on the bridge. Spiro and fused ringsare also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-memberedmonocyclic or bicyclic aromatic ring which consists of carbon atoms andone or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur.In the case of bicyclic heterocyclic aromatic rings, only one of the tworings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be(e.g., quinoline). The second ring can also be fused or bridged asdefined above for heterocycles. The nitrogen atom can be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The nitrogen and sulfur heteroatoms can optionally be oxidized(i.e., N→O and S(O)_(p), wherein p=1 or 2). In certain compounds, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1.

Examples of heterocycles include, but are not limited to, acridinyl,azabicyclooctanonyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, benzodioxoly, benzooxadiazoly,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, cycloheptyl, decahydroquinolinyl, dihydrobenzodioxinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolidinylimine, imidazolinyl,imidazolyl, imidazolonyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenztriazoly,methylfuranyl, methylimidazolyl, methylthiazolyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolidinonyl, oxazolyl, oxindolyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperazinonyl, piperidinyl, piperidonyl, 4-piperidonyl,piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl, pyrimidinyl,pyrroldionyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, thiomorpholinyldioxidyl,triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention can be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

As used herein, “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

As used herein, the term “patient”, as used herein, means the human oranimal (in the case of an animal, more typically a mammal) subject thatwould be subjected to a surgical or invasive medical procedure. Suchpatient or subject could be considered to be in need of the methods ofreducing the risk of or preventing the infection due to a surgicalprocedure or an invasive medical procedure. Such patient or subject canalso be considered to be in need of peri-operative prophylaxis.

As used herein, the term “treating” means to provide a therapeuticintervention to cure or ameliorate an infection.

As used herein, the term “preventing”, as used herein means, tocompletely or almost completely stop an infection from occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection. Preventing can also includeinhibiting, i.e. arresting the development, of an infection.

As used herein, the term “reducing the risk of”, as used herein, meansto lower the likelihood or probability of an infection occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection.

As used herein, “unsaturated” refers to compounds having at least onedegree of unsaturation (e.g., at least one multiple bond) and includespartially and fully unsaturated compounds.

As used herein, the term “effective amount” refers to an amount of acompound, or a combination of compounds, of the present inventioneffective when administered alone or in combination as an antimicrobialagent. For example, an effective amount refers to an amount of thecompound present in a composition, a formulation or on a medical devicegiven to a recipient patient or subject sufficient to elicit biologicalactivity, for example, anti-infective activity, such as e.g.,anti-microbial activity, anti-bacterial activity, anti-fungal activity,anti-viral activity, or anti-parasitic activity.

The term “prophylactically effective amount” means an effective amountof a compound or compounds, of the present invention that isadministered to prevent or reduce the risk of an infection due to asurgical procedure or an invasive medical procedure.

It is to be further understood that the representations for “HydrogenBond Acceptor-Hydrogen Bond Acceptor—Hydrogen Bond Donor” and “HydrogenBond Acceptor—Hydrogen Bond Acceptor—Hydrogen Bond Acceptor” are meantto indicate the relative orientation of the hydrogen bond acceptors anddonor and not meant to limit that such groups are directly connectedtogether as it is contemplated that additional atoms or groups of atomscan be included between such groups.

In the specification, the singular forms also include the plural, unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. In the case of conflict, the present specificationwill control. As used herein, “mammal” refers to human and non-humanpatients.

As used herein, the term “therapeutically effective amount” refers to acompound, or a combination of compounds, of the present inventionpresent in or on a recipient in an amount sufficient to elicitbiological activity, for example, anti-microbial activity, anti-fungalactivity, anti-viral activity, anti-parasitic activity, anti-diarrhealactivity, and/or anti-proliferative activity. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22.pp. 27-55 (1984), occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased anti-proliferative and/or anti-infective effect,or some other beneficial effect of the combination compared with theindividual components.

As used herein, the term “RNA microhelix binding site” refers to theribofunctional locus of the large ribosomal subunit occupied by the RNAmicrohelix of Formula III. The RNA microhelix binding site defines atleast a portion of or overlaps with the E-site.

As used herein, the term “A-site” refers to the ribofunctional locusoccupied by an aminoacyl-tRNA molecule immediately prior to itsparticipation in the peptide-bond forming reaction.

As used herein, the term “E-site” refers to the ribofunctional locusoccupied by a deacylated tRNA molecule following its participation inthe peptide-bond forming reaction.

As used herein, the term “P-site” refers to the ribofunctional locusoccupied by a peptidyl-tRNA at the time it participates in thepeptide-bond forming reaction.

As used herein, the term “A-space” refers to the portion of the A-sitewithin the peptidyl transferase center in which the amino acid portionof the aminoacylated t-RNA binds, or alternatively the portion of theA-site in which the oxazolidinone ring of linezolid binds.

As used herein and in reference to a ribosome or ribosomal subunit, theterms “a portion of” or “a portion of the three-dimensional structureof” are understood to mean a portion of the three-dimensional structureof a ribosome or ribosomal subunit, including charge distribution andhydrophilicity/hydrophobicity characteristics, formed by at least three,more preferably at least three to ten, and most preferably at least tenamino acid residues and/or nucleotide residues of the ribosome orribosomal subunit. The residues forming such a portion can be, forexample, (i) contiguous residues based upon, for example, a primarysequence of a ribosomal RNA or ribosomal protein, (ii) residues whichform a contiguous portion of the three-dimensional structure of theribosome or ribosomal subunit, or (c) a combination thereof. As usedherein and in reference to the RNA microhelix, the terms “a portion of”or “a portion of the three-dimensional structure of” are understood tomean a portion of the three-dimensional structure of RNA microhelix,including charge distribution and hydrophilicity/hydrophobicitycharacteristics, formed by at least three, more preferably at leastthree to ten atoms of one or more core residues of Formula III. Theatoms forming such a portion can be, for example, (i) solventinaccessible atoms buried within the core of the RNA microhelix, (ii)solvent accessible atoms of the RNA microhelix, or (iii) a combinationthereof.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present invention also consistessentially of, or consist of, the recited components, and that theprocesses of the present invention also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

2. COMPOUNDS OF THE INVENTION

In one aspect, the invention relates to a compound having the structure:

wherein

is a chemical moiety selected from:

wherein U is selected from the group consisting of CR³R³, O, NR⁴, orS(O)_(n), C═O, C═NOR³, alternatively, two R³s are taken together to forma carbonyl,V is independently selected from —CR^(4a)— or —N—;wherein

represents a fused 5 to 7 member saturated, unsaturated, or aromaticcarbocyclic or heterocyclic ring system;W is O, NR¹, NOR¹, or S, alternatively W═ is selected from thecombination of HO— and H— both attached to the same carbon atom or thecombination of (C₁₋₈ alkyl)O— and H— both attached to the same carbonatom;

represents a single bond or a double bond such that when

is a single bond, X is selected from O, NR², and S(O) and Y is C—R³, andwhen

is a double bond, X is N and Y is a carbon atom,Z is selected from the group consisting of O, NR⁴, or S(O)_(n),R¹ is selected from H and C₁₋₈ alkyl,R² is selected from H and C₁₋₈ alkyl,R³ is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,n is 0, 1, or 2,alternatively, -G-H-J is selected from:

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b) wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;wherein n is 0, 1, or 2;alternatively, -G-H-J is selected from

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isa C or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;C-B-A-, -D-E-F, and -G-H-J are chemical moieties, whereinA, D and G are independently selected from the group consisting of:

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   (e) —O—, (f) —NR⁶—, (g) —S(O)_(p)—, (h) —C(O)—, (i) —C(O)O—, (j)        —OC(O)—, k) —OC(O)O—, (l) —C(O)NR⁶—, (m) —NR⁶CO—, (n)        —NR⁶C(O)NR⁶—, (o) —C(═NR⁶)—, (p) —C(═NR⁶)O—, (q) —OC(═NR⁶)—, (r)        —C(═NR⁶)NR⁶—, (s) —NR⁶C(═NR⁶)—, (t) —C(═S)—, (u) —C(═S)NR⁶—, (v)        —NR⁶C(═S)—, (w) —C(O)S—, (x) —SC(O)—, (y) —OC(═S)—, (z)        —C(═S)O—, (aa) —NR⁶(CNR⁹)NR)NR—, (bb) —CR⁶R⁶C(O)—, (cc)        —C(O)NR⁶(CR⁶R⁶)_(t)—, (dd) a 3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, (ee) a 3-14 member saturated, unsaturated, or aromatic        carbocycle, and (ff) —(CR⁶R⁶)_(t)—        wherein (dd) or (ee) is optionally substituted with one or more        R⁵ groups;        B, E, and H are independently selected from the group consisting        of:    -   (a) a single bond,    -   (b) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,    -   (c) a 3-14 member saturated, unsaturated, or aromatic        carbocycle, wherein (b) or (c) is optionally substituted with        one or more R⁵ groups;    -   (d) —(C₁₋₈ alkyl)-, (e) —(C₂₋₈ alkenyl)-, (f) —(C₂₋₈ alkynyl)-,        wherein        -   i) 0-4 carbon atoms in any of (d)-(f) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (d)-(f) immediately above optionally is            substituted with one or more R³ groups, and        -   iii) any of (d)-(f) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   and (g) —(CR⁶R⁶)—        C, F, and J are independently selected from the group consisting        of:    -   (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h)        —CN, (i) —N₃ (j) —NO₂, (k) —NR⁶(CR⁶R⁶)_(t)R⁸, (l) —OR⁸, (m)        —S(O)_(p)(CR⁶R⁶)_(t)R⁸, (n) —C(O)(CR⁶R⁶)_(t)R⁸, (o)        —OC(O)(CR⁶R⁶)_(t)R⁸, (p) —SC(O)(CR⁶R⁶)_(t)R⁸, (q)        —C(O)O(CR⁶R⁶)_(t)R⁸, (r) —NR⁶C(O)(CR⁶R⁶)_(t)R⁸, (s)        —C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁸, (u)        —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁸, (v) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁸, (w)        —C(═NOR⁸)(CR⁶R⁶)_(t)R⁸, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁸, (y)        —OC(O)NR⁶(CR⁶R⁶)_(t)R⁸, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (aa)        —NR⁶S(O)_(p)(CR⁶R⁶)R⁸, (bb) —S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (cc)        —NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (dd) —NR⁶R⁸, (ee)        —NR⁶(CR⁶R⁶)_(t)R⁸, (ff) —OH, (gg) —NR⁸R⁸, (hh) —OCH₃, (ii)        —S(O)_(p)R⁸, (jj) —NC(O)R⁸, (kk) —NR⁶C(NR⁶)NR⁶R⁸, (ll) a C₁₋₈        alkyl group, (mm) a C₂₋₈ alkenyl group, (nn) a C₂₋₈ alkynyl        group, (oo) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, (pp) a 3-14        member saturated, unsaturated, or aromatic carbocycle, (qq)        —(CR⁶R⁶)_(t)NR⁶(CR⁶R⁶)_(t)R⁸, (rr)        —N[(CR⁶R⁶)_(t)R⁸][C═O(CR⁶R⁶)_(t)R⁸], (ss)        —(CR⁶R⁶)_(t)N[(CR⁶R⁶)_(t)R⁸][(CR⁶R⁶)_(t)R⁸], (tt)        —(CR⁶R⁶)_(t)NR⁶(C═O)(CR⁶R⁶)_(t)R⁸, (uu) -haloalkyl, (vv)        —C(O)(CR⁶)[(CR⁶R⁶)_(t)R⁸]R⁸, (ww) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (xx)        —(CR⁶R⁶)_(t)C(O)O(CR⁶R⁶)_(t)R⁸, (yy) —NR⁶C(O)CR⁸R⁸R⁸, (zz)        —N[(CR⁶R⁶)_(t)R⁸]C(O)R⁸, and (aaa) —S(O)_(p)NR⁸R⁸;        wherein (ll) through (pp) is optionally substituted with one or        more R⁷ groups;        R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e)        I, (f) —CF₁, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁸, (k)        —OR⁸, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈        alkenyl, (o) —C₁₋₈ alkynyl, (p) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic carbocycle), (r)        -haloalkyl, (s) —SR⁶, (t) -3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic        carbocycle; alternatively, two R⁵ groups are taken together to        form a carbocycle;

wherein (m) through (r) and (t) through (u) is optionally substitutedwith one or more R;

R⁶ is selected from (a) hydrogen, (b) —C₁₋₈ alkyl or alternatively twoR⁶ groups are taken together to form a carbocycle, (c) -haloalkyl, (d)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and (e) -3-14 member saturated, unsaturated, oraromatic carbocycle;wherein (b) through (e) is optionally substituted with one or more R⁸;R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl,(s) —NR⁶R⁸, (t) —OR⁸, (u) —(CR⁶R⁶)_(t)NR⁶R⁸, (v) —CR⁶R⁸R⁸, (w) —SR⁶, (x)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or aromaticcarbocycle, (z) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (aa) —S(O)_(p)R⁸, (bb)—NR⁶C(O)NR⁶R⁶, (cc) —NR⁶C(O)R⁶, and (dd) —C(═NR⁶)NR⁶R⁶;

wherein (m) through (q) and (x) through (y) are optionally substitutedwith one or more R⁹:

R⁸ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁹, (k) —OR⁸, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, (s) -3-14 member saturated, unsaturated, or aromatic carbocycle,(t) -haloalkyl, (u) —C(O)(CR⁶R⁶)_(t)R⁹, (v) —SR⁶, (w)—OC(O)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)NR⁶R⁹, (y) —NR⁶C(O)R⁹, (z)—NR⁶(CNR⁹)(NR⁶R⁶), (aa) —ONR⁶(CNR⁶)NR⁶R⁶, (bb) —C(═NR⁹)NR⁶R⁶, (cc)—S(O)_(p)R⁹, (dd) —(CR⁶R⁶)_(t)C(O)NR⁶R⁹, (ee) —(CR⁶R⁶)_(t)OR⁹, and (f)—(CR⁶R⁶)_(t)NR⁶R⁹;

wherein (m) through (s) is optionally substituted with one or more R⁹;

R⁹ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R¹⁰, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶) NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R¹⁰, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR¹⁰, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁶, (ff) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R¹⁰;

wherein (n) through (r) and (z) through (aa) is optionally substitutedwith one or more R¹⁰;

R¹⁰ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R⁶, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR⁶, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁶, (f) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R⁶;

optionally, wherein either the group -E-F or the group -G-H-J is absent,but both -D-E-F and -G-H-J are not simultaneously absent;

p is 0, 1, or 2, andt is 0, 1, 2, or 3,or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

further comprises a hydrogen bond donor moiety or an additional hydrogenbond acceptor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

is a chemical moiety comprising at least two hydrogen bond acceptormoieties and at least one hydrogen bond donor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein the hydrogen bond acceptor moieties and hydrogen bond donormoieties are in the orientation of

Hydrogen Bond Acceptor—Hydrogen Bond Acceptor—Hydrogen Bond Donor. Asused above the term “in the orientation of” does not mean that thehydrogen bond donor or acceptor moieties are necessarily directlyconnected together as there can be other intervening atoms or groups ofatoms in between the hydrogen bond donor or acceptor moieties.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein the hydrogen bond acceptor moieties are within 5 Å of each otherand the hydrogen bond donor moiety is within 5 Å of a hydrogen bondacceptor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein the hydrogen bond acceptor moieties are within 3 Å of each otherand the hydrogen bond donor moiety is within 3 Å of a hydrogen bondacceptor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein the hydrogen bond acceptor moieties are comprised within a ringstructure, wherein said ring structure is a single ring structure or afused multiple ring structure.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

is a chemical moiety comprising at least three hydrogen bond acceptormoieties.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein the hydrogen bond acceptor moieties are in the orientation of

Hydrogen Bond Acceptor—Hydrogen Bond Acceptor—Hydrogen Bond Acceptor. Asused above the term “in the orientation of” does not mean that thehydrogen bond donor or acceptor moieties are necessarily directlyconnected together as there can be other intervening atoms or groups ofatoms in between the hydrogen bond acceptor moieties.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein each hydrogen bond acceptor moiety is within about 5 Å of atleast one other hydrogen bond acceptor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein each hydrogen bond acceptor moiety is within about 3 Å of atleast one other hydrogen bond acceptor moiety.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein at least two of the hydrogen bond acceptor moieties arecomprised within a ring structure, wherein said ring structure is asingle ring structure or a fused multiple ring structure.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein said hydrogen bond acceptor moieties are independently selectedfrom the group consisting of a carbonyl group, a thiocarbonyl group, animine group, an alkyl substituted imine group, a sulfoxide group, asulfone group, an oxime group, an alkyl substituted oxime group, ahydrazone group, a monoalkyl or dialkyl substituted hydrazone group, anoxygen ether (—O—) group, a sulfide, also known as a thioether group(—S—), a hydroxy group, an alkoxy group, an amino group, a monoalkyl ordialkyl substituted amino group, and a nitro group.

In some embodiments, the present invention relates to a compound of apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein said hydrogen bond donor moiety is selected from the groupconsisting of a hydroxy group, a thiol group, an amino group, and amonosubstituted amino group.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

comprises the structural moiety

W is O, NR¹, NOR¹, or S, alternatively W═ is selected from thecombination of HO— and H— both attached to the same carbon atom or thecombination of (C₁₋₈ alkyl)O— and H— both attached to the same carbonatom;

represents a single bond or a double bond such that when

is a single bond, X is selected from O, NR², and S(O)_(n) and Y is C—R³,and when

is a double bond, X is N and Y is a carbon atom,Z is selected from the group consisting of O, NR⁴, or S(O)_(n),R¹ is selected from H and C₁₋₈ alkyl,R² is selected from H and C₁₋₈ alkyl,R³ is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,n is 0, 1, or 2.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein W is O, NR¹, NOR¹, or S; wherein R¹ is selected from H and C₁₋₆alkyl.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

comprises the structural moiety

wherein Z is selected from the group consisting of O, NR⁴, or S(O)_(n);R⁴ is selected from H and C₁₋₆ alkyl,andn is 0, 1, and 2.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

comprises the structural moiety

wherein R⁴ is selected from H and C₁₋₆ alkyl.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein R⁴ is H.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

comprises a cytosine or isocytosine moiety or a derivative thereof.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

comprises the structural moiety

wherein U is selected from the group consisting of CR³R³, O, NR⁴, orS(O)_(n), C═O, C═NOR³, alternatively, two R³s are taken together to forma carbonyl,V is independently selected from —CR^(4a)— or —N—;wherein

represents a used 5 to 7 member saturated, unsaturated, or aromaticcarbocyclic or heterocyclic ring system;W is O, NR¹, NOR¹, or S, alternatively W═ is selected from thecombination of HO— and H— both attached to the same carbon atom or thecombination of (C₁₋₈ alkyl)O— and H— both attached to the same carbonatom;

represents a single bond or a double bond such that when

is a single bond, X is selected from O, NR², and S(O)_(n) and Y is C—R³,and when

is a double bond, X is N and Y is a carbon atom,Z is selected from the group consisting of O, NR⁴, or S(O)_(n),R¹ is selected from H and C₁₋₈ alkyl,R² is selected from H and C₁₋₈ alkyl,R³ is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,R^(4a) is selected from H and C₁₋₈ alkyl,n is 0, 1, or 2.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein U is selected from the group consisting of CR³R³, O, NR⁴, orS(O)_(n), C═O, C═NOR³, alternatively, two R³s are taken together to forma carbonyl,V is independently selected from —CR^(4a)— or —N—;wherein

represents a fused 5 to 7 member saturated, unsaturated, or aromaticcarbocyclic or heterocyclic ring system;W is O, NR¹, NOR¹, or S, alternatively W═ is selected from thecombination of HO— and H— both attached to the same carbon atom or thecombination of (C₁₋₈ alkyl)O— and H— both attached to the same carbonatom;

represents a single bond or a double bond such that when

is a single bond, X is selected from O, NR², and S(O)_(n) and Y is C—R³,and when

is a double bond, X is N and Y is a carbon atom,Z is selected from the group consisting of O, NR⁴, or S(O)_(n),R¹ is selected from H and C₁₋₈ alkyl,R² is selected from H and C₁₋₈ alkyl,R³ is selected from H and C₁₋₈ alkyl,R⁴ is selected from H and C₁₋₈ alkyl,R^(4a) is selected from H and C₁₋₈ alkyl,n is 0, 1, or 2,alternatively, -G-H-J is selected from

wherein each H and J are independently selected,alternatively, -G-H-J is selected from:

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b) wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle;J is selected from NH₂, NH(C₁₋₈ alkyl). N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;wherein n is 0, 1, or 2;alternatively, -G-H-J is selected from

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isC or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;C-B-A-, -D-E-F, and -G-H-J are chemical moieties, whereinA, D and G are independently selected from the group consisting of:

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   (e) —O—, (f) —NR⁶—, (g) —S(O)_(p)—, (h) —C(O)—, (i) —C(O)O—, (j)        —OC(O)—, k) —OC(O)O—, (l) —C(O)NR⁶—, (m) —NR⁶CO—, (n)        —NR⁶C(O)NR⁶—, (o) —C(═NR⁶)—, (p) —C(═NR⁶)O—, (q) —OC(═NR⁶)—, (r)        —C(═NR⁶)NR⁶—, (s) —NR⁶C(═NR⁶)—, (t) —C(═S)—, (u) —C(═S)NR⁶—, (v)        —NR⁶C(═S)—, (w) —C(O)S—, (x) —SC(O)—, (y) —OC(═S)—, (z)        —C(═S)O—, (aa) —NR⁶(CNR⁶)NR⁶—, (bb) —CR⁶R⁶C(O)—, (cc)        —C(O)NR⁶(CR⁶R⁶)_(t)—, (dd) a 3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur,    -   (ee) a 3-14 member saturated, unsaturated, or aromatic        carbocycle, and    -   (f) —(CR⁶R⁶)_(t)—,        wherein (dd) or (cc) is optionally substituted with one or more        R⁵ groups;        B, E, and H are independently selected from the group consisting        of:    -   (a) a single bond,    -   (b) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,    -   (c) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,        wherein (b) or (c) is optionally substituted with one or more R⁵        groups;    -   (d) —(C₁₋₈ alkyl)-, (e) —(C₂₋₈ alkenyl)-, (f) —(C₂₋₈ alkynyl)-,        wherein        -   i) 0-4 carbon atoms in any of (d)-(f) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (d)-(f) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (d)-(f) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;            -   and (g) —(CR⁶R⁶)—,                C, F, and J are independently selected from the group                consisting of:    -   (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h)        —CN, (i) —N(j) —NO₂, (k) —NR⁶(CR⁶R⁶)_(t)R⁵, (l) —OR⁸, (m)        —S(O)_(p)(CR⁶R⁶)_(t)R⁸, (n) —C(O)(CR⁶R⁶)R⁸, (o)        —OC(O)(CR⁶R⁶)_(t)R⁸, (p) —SC(O)(CR⁶R⁶)_(t)R⁸, (q)        —C(O)O(CR⁶R⁶)_(t)R⁸, (r) —NR⁶C(O)(CR⁶R⁶)_(t)R⁸, (s)        —C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁸, (u)        —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁸, (v) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁸, (w)        —C(═NOR⁸)(CR⁶R⁶)_(t)R⁸, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁸, (y)        —OC(O)NR⁶(CR⁶R⁶)_(t)R⁸, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (aa)        —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁸, (bb) —S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (cc)        —NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (dd) —NR⁶R⁸, (ee)        —NR⁶(CR⁶R⁶)_(t)R⁸, (ff) —OH, (gg) —NR⁸R⁸, (hh) —OCH₃, (ii)        —S(O)_(p)R⁸, (jj) —NC(O)R⁸, (kk) —NR⁶C(NR⁶)NR⁶R⁸, (ll) a C₁₋₈        alkyl group, (mm) a C₂₋₈ alkenyl group, (nn) a C₂₋₈alkynyl        group, (oo) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, (pp) a 3-14        member saturated, unsaturated, or aromatic carbocycle, (qq)        —(CR⁶R⁶)_(t)NR⁶(CR⁶R⁶)_(t)R⁸, (rr)        —N[(CR⁶R⁶)_(t)R⁸][C═O(CR⁶R⁶)_(t)R⁸], (ss)        —(CR⁶R⁶)_(t)N[(CR⁶R⁶)_(t)R⁸][(CR⁶R⁶)_(t)R⁸], (tt)        —(CR⁶R⁶)_(t)NR⁶(C═O)(CR⁶R⁶)_(t)R⁸, (uu) -haloalkyl, (vv)        —C(O)(CR⁶)[(CR⁶R⁶)_(t)R⁸]R⁸, (ww) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (xx)        —(CR⁶R⁶)_(t)C(O)O(CR⁶R⁶)_(t)R⁸, (yy) —NR⁶C(O)CR⁸R⁸R⁸, (zz)        —N[(CR⁶R⁶)_(t)R⁸]C(O)R⁸, and (aaa) —S(O)_(p)NR⁸R⁸;        wherein (ll) through (pp) is optionally substituted with one or        more R⁷ groups;        R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e)        I, (f) —CF₃, (g) —CN, (h) —N: (i) —NO₂, (j) —NR⁶R⁶, (k)        —OR⁸, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈        alkenyl, (o) —C₁₋₈ alkynyl, (p) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14 member        saturated, unsaturated, or aromatic carbocycle), (r)        -haloalkyl, (s) —SR⁶, (t) -3-14 member saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic        carbocycle;

wherein (m) through (r) and (t) through (u) is optionally substitutedwith one or more R⁸;

R⁶ is selected from (a) hydrogen, (b) —C₁₋₈ alkyl or alternatively twoR⁶ groups are taken together to form a carbocycle, (c) -haloalkyl, (d)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and (e) -3-14 member saturated, unsaturated, oraromatic carbocycle;wherein (b) through (e) is optionally substituted with one or more R⁸;R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl,(s) —NR⁶R⁸, (t) —OR⁸, (u) —(CR⁶R⁶)_(t)NR⁶R⁸, (v) —CR⁶R⁸R⁸, (w) —SR⁶, (x)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or aromaticcarbocycle, (z) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (aa) —S(O)_(p)R⁸, (bb)—NR⁶C(O)NR⁶R⁶, (cc) —NR⁶C(O)R⁶, and (dd) —(═NR⁶)NR⁶R⁶;

wherein (m) through (q) and (x) through (y) are optionally substitutedwith one or more R⁹;

R⁸ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁹, (k) —OR⁸, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, (s) -3-14 member saturated, unsaturated, or aromatic carbocycle,(t) -haloalkyl, (u) —C(O)(CR⁶R⁶)_(t)R⁹, (v) —SR⁶, (w)—OC(O)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)NR⁶R⁹, (y) —NR⁶C(O)R⁹, (z)—NR⁶(CNR⁹)(NR⁶R⁶), (aa) —ONR⁶(CNR⁶)NR⁶R⁶, (bb) —C(═NR⁹)NR⁶R⁶, (cc)—S(O)_(p)R⁹, (dd) —(CR⁶R⁶)_(t)C(O)NR⁶R⁹, (ee) —(CR⁶R⁶)_(t)OR⁹, and (ff)—(CR⁶R⁶)_(t)NR⁶R⁹;

wherein (m) through (s) is optionally substituted with one or more R⁹;

R⁹ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R¹⁰, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R¹⁰, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR¹⁰, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁶, (ff) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R¹⁰;

wherein (n) through (r) and (z) through (aa) is optionally substitutedwith one or more R¹⁰;

R¹⁰ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)—CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)_(t)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 membersaturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R⁶, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR⁶, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁸, (ff) —O(CR⁶R⁶)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R⁶;

optionally, wherein either the group -D-E-F or the group -G-H-J isabsent, but both -D-E-F and -G-H-J are not simultaneously absent;

p is 0, 1, or 2, andt is 0, 1, 2, or 3,or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, wherein A isselected from

-   -   (a) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, and    -   (b) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,    -   (c) a single bond,        wherein (a) or (b) is optionally substituted with one or more R⁵        groups;        B is selected from (a) —(C₁₋₈ alkyl)-, (b) —(C₂₋₈ alkenyl)-, (c)        —(C₂₋₈ alkynyl)-, (d) a single bond, wherein    -   i) 0-4 carbon atoms in any of (a)-(c) immediately above        optionally is replaced by a moiety selected from the group        consisting of —O—, —S(O)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,        —S(O)_(p)NR⁶—, and —NR⁶S(O)_(p)NR⁶—,    -   ii) any of (a)-(c) immediately above optionally is substituted        with one or more R⁵ groups, and    -   iii) any of (a)-(c) immediately above optionally is substituted        with —(C₁₋₈ alkyl)-R⁵ groups, and        C is selected from (a) NH₂, (b) —NHC(═NH)NH₂ and (c) hydrogen,        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, wherein A isselected from

-   -   (a) a 4-7 member saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur, and    -   (b) a 4-7 member saturated, unsaturated, or aromatic carbocycle,    -   (c) a single bond,        wherein (a) or (b) is optionally substituted with one or more R⁵        groups;        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, wherein A isselected from azepanyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, phenyl, pyridinyl, cyclohexenyl, cyclohexadienyl,dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl,azetidinyl, pyrrolidinyl, piperidinyl and piperidenyl;

wherein any of A immediately above optionally is substituted with one ormore R⁵ groups;alternatively, A is a single bond;B is selected from (a) —(C₁₋₈ alkyl)-, wherein

-   -   i) 0-4 carbon atoms in (a) immediately above optionally is        replaced by a moiety selected from the group consisting of —O—,        —S(O)_(p)—, —NR⁶—, —(C═O)—, —S(O)_(p)NR⁶—, and —NR⁶S(O)_(p)NR⁶—,    -   ii) (a) immediately above optionally is substituted with one or        more R⁵ groups, and    -   iii) (a) immediately above optionally is substituted with —(C₁₋₈        alkyl)-R⁵ groups; and        alternatively, B is a single bond;        C is selected from (a) NH₂, (b) —NHC(═NH)NH₂ and (c) hydrogen;        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, G is selectedfrom

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   (e) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, and    -   (f) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,        wherein (e) or (f) is optionally substituted with one or more R⁵        groups;        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, G selectedfrom

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;            wherein p is 0, 1, or 2,            or a pharmaceutically acceptable salt, ester, tautomer, or            prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, wherein

is selected from:

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compoundaccording to formula III, III, IV, VI, VII, or VIII, wherein

is selected from

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, wherein -G-H-Jis selected from:

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, K, U, V, W, X, Y, and Z are as definedin formula (I) immediately above, or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

represents a fused six member saturated, unsaturated or aromaticcarbocyclic or heterocyclic ring system.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (I), wherein Q¹, Q², Q³, and Q⁴ are independently selected froma nitrogen atom, a carbon atom, or CH, wherein -D-E-F or -G-H-J, when itis present, is attached to a carbon, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -G-H-J, U, V, W, X, Y, and Z are as defined in formula(I),wherein Q^(1a), Q^(2a), and Q^(4a) are independently selected from anitrogen atom, a carbon atom, or CH, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (II),or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

represents a fused six membered saturated, unsaturated or aromaticcarbocyclic or heterocyclic ring system.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (II),wherein Q¹, Q², Q³, and Q⁴ are independently selected from a nitrogenatom, a carbon atom, or CH, wherein -D-E-F or -G-H-J, when it ispresent, is attached to a carbon, or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -G-H-J, U, V, W, X, Y, and Z are as defined in formula(II),wherein Q¹, Q², and Q⁴ are independently selected from a nitrogen atom,a carbon atom, or a pharmaceutically acceptable salt, ester, tautomer,or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -G-H-J, V, W, X, and Y are as defined in formula (I),wherein T¹ is CH or NH, with the proviso that when T¹ is NH, -D-E-F isabsent; or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (I) or formula (II),or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound havingthe formula (I) or (II), wherein

represents a fused 6 member aromatic carbocyclic or heterocyclic ringsystem; or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (I) or formula (II), or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y, and Z are as defined informula (I), or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula V, VI, VII, or VIII:

wherein C-B-A-, -D-E-F, and -G-H-J are as defined in formula (I), or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A-, -D-E-F, and -G-H-J are as defined in formula (I), or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein D and E are single bonds, and F is hydrogen; wherein C-B-A- and-G-H-J are as defined in formula (i), or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A- and -G-H-J are as defined in formula (I), or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A- and -G-H-J are as defined in formula (I), or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein A is selected from

-   -   (a) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, and    -   (b) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,    -   (c) a single bond,        wherein (a) or (b) is optionally substituted with one or more R⁵        groups;        B is selected from (a) —(C₁₋₈ alkyl)-, (b) —(C₂₋₈ alkenyl)-, (c)        —(C₂₋₈ alkynyl)-, (d) a single bond, wherein    -   i) 0-4 carbon atoms in any of (a)-(c) immediately above        optionally is replaced by a moiety selected from the group        consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,        —S(O)_(p)NR⁶—, and —NR⁶S(O)_(p)NR⁶—,    -   ii) any of (a)-(c) immediately above optionally is substituted        with one or more R⁵ groups, and    -   iii) any of (a)-(c) immediately above optionally is substituted        with —(C₁₋₈ alkyl)-R⁵ groups, and        C is selected from (a) NH₂, (b) —NHC(═NH)NH₂ and (c) hydrogen,        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein A is selected from azepanyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, phenyl, pyridinyl, cyclohexenyl,cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl,tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl andpiperidenyl;wherein any of A immediately above optionally is substituted with one ormore R⁵ groups;alternatively, A is a single bond;B is selected from (a) —(C₁₋₈ alkyl)-, wherein

-   -   i) 0-4 carbon atoms in (a) immediately above optionally is        replaced by a moiety selected from the group consisting of —O—,        —S(O)_(p)—, —NR⁶—, —(C═O)—, —S(O)_(p)NR⁶—, and —NR⁶S(O)_(p)NR⁶—,    -   ii) (a) immediately above optionally is substituted with one or        more R⁵ groups, and    -   iii) (a) immediately above optionally is substituted with —(C₁₋₈        alkyl)-R⁵ groups; and        alternatively, B is a single bond;        C is selected from (a) NH₂, (b) —NHC(═NH)NH₂ and (c) hydrogen;        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein C-B-A- is selected from the group consisting of:

hydrogen,

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound havingthe formula:

wherein G is selected from

-   -   (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)        —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;    -   (e) a 3-14 member saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, and    -   (f) a 3-14 member saturated, unsaturated, or aromatic        carbocycle,        wherein (e) or (f) is optionally substituted with one or more R⁵        groups;        or a pharmaceutically acceptable salt, ester, tautomer, or        prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula:

-   -   wherein G is selected from (a) a single bond, (b) —(C₁₋₈        alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d) —(C₂₋₈ alkynyl)-, wherein        -   i) 0-4 carbon atoms in any of (b)-(d) immediately above            optionally is replaced by a moiety selected from the group            consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,            —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—,        -   ii) any of (b)-(d) immediately above optionally is            substituted with one or more R⁵ groups, and        -   iii) any of (b)-(d) immediately above optionally is            substituted with —(C₁₋₈ alkyl)-R⁵ groups;            wherein p is 0, 1, or 2,            or a pharmaceutically acceptable salt, ester, tautomer, or            prodrug thereof.

In some embodiments, the present invention relates to a compound havingthe formula

wherein

is selected from:

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound havingthe formula

wherein -G-H-J is selected from:

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compound havingthe formula

wherein

is selected from:

or -G-H-J is selected from:

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b) wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H;wherein n is 0, 1, or 2;alternatively, -G-H-J is selected from

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isa C or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3;J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃,NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═N)H;or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.

In some embodiments, the present invention relates to a compoundcontaining R⁵, wherein R⁵ is selected from (a) hydrogen, (b) F, (c) Cl,(d) Br, (e) I, (f) —CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NH₂, (k) —OR⁶,(l) —NHC(NH)NH₂, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl,(s) —SR⁶, (t) -3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and (u) -3-14 membersaturated, unsaturated, or aromatic carbocycle; alternatively, two R⁵groups are taken together to form a carbocycle; or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compoundcontaining R⁶, wherein R⁶ is selected from (a) hydrogen, (b) —C₁₋₈ alkylor alternatively two R⁶ groups are taken together to form a carbocycle,(c) -haloalkyl, (d) -3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and (e) -3-14 membersaturated, unsaturated, or aromatic carbocycle; or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, II, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein -D-E-F represents hydrogen.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein W, when it is present, is O, NR¹, NOR¹, or S.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein

when it is present, is a double bond and X is N and Y is a carbon atom.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein R^(4a), when it is present, is H.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein Z, when it is present, is NR⁴.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,wherein R⁴ is H.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,that binds to a ribosome.

In some embodiments, the present invention relates to a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof,that binds to the ribosome wherein the ribosome is a bacterial ribosome.

In some embodiments, the present invention relates to a compoundaccording to any of the compounds in Table 1 or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a pharmaceuticalcomposition comprising a compound of the invention, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,and a pharmaceutically acceptable carrier.

In some embodiments, the present invention relates to a method fortreating, preventing or reducing the risk of a disease state in a humanor animal comprising administering to a human or animal in need thereofan effective amount of a compound of the invention or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a method oftreating a microbial infection in a human or animal comprisingadministering to the human or animal an effective amount of a compoundof the invention, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof.

In some embodiments, the present invention relates to the use of acompound of the invention, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, in the manufacture of a medicament fortreating a microbial infection in a human or animal.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a microbial infection in ahuman or animal comprising administering to the human or animal aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof, or to the use of acompound of the invention, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, in the manufacture of a medicament fortreating, preventing, or reducing the risk of a microbial infection,

wherein the microbial infection is selected from the group consistingof.

-   -   a skin infection, a Gram positive infection, a Gram negative        infection, nosocomial pneumonia, community acquired pneumonia,        post-viral pneumonia, hospital acquired pneumonia/ventilator        associated pneumonia, a respiratory tract infection such as        CRTI, acute pelvic infection, a complicated skin and skin        structure infection, a skin and soft tissue infection (SSTI)        including uncomplicated skin and soft tissue infections (uSSTI)s        and complicated skin and soft tissue infections, an abdominal        infection, a complicated intra-abdominal infection, a urinary        tract infection, bacteremia, septicemia, endocarditis, an        atrio-ventricular shunt infection, a vascular access infection,        meningitis, surgical prophylaxis, a peritoneal infection, a bone        infection, a joint infection, a methicillin-resistant        Staphylococcus aureus infection, a vancomycin-resistant        Enterococci infection, a linezolid-resistant organism infection,        a Bacillus anthracis infection, a Francisella tularensis        infection, a Yersinia pestis infection, and tuberculosis.

In some embodiments, the present invention relates to a method or usewherein the compound of the invention, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof, is administered otically,ophthalmically, nasally, orally, parenterally, topically, orintravenously.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a complicatedintra-abdominal infection in a human or animal comprising administeringto the human or animal an effective amount of a compound according toformula I, II, III, IV, V, VI, VII, or VIII, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof, or to the use of acompound according to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,in the manufacture of a medicament for treating, preventing, or reducingthe risk of a complicated intra-abdominal infection, wherein thecomplicated intra-abdominal infection is selected from polymicrobialinfections such as abscess due to Escherichia coli, Clostridiumclostridioforme, Eubacterium lentum, Peptastreptococcus spp.,Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Streptococcusanginosus, Streptococcus constellatus, Enterococcus faecalis, Proteusmirabilis, or Clostridium perfringens.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a complicated skin and skinstructure infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound according to formulaI, II, III, IV, V, VI, VII, or VIII, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof, or to the use of a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,in the manufacture of a medicament for treating, preventing, or reducingthe risk of a complicated skin and skin structure infection

wherein the complicated skin and skin structure infection is selectedfrom diabetic foot infections without osteomyelitis due toStaphylococcus aureus (methicillin susceptible and resistant isolates),Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli,Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis,Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotellabivia.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a community acquiredpneumonia in a human or animal comprising administering to the human oranimal an effective amount of a compound according to formula I, II,III, IV, V, VI, VII, or VIII, or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof, or to the use of a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,in the manufacture of a medicament for treating, preventing, or reducingthe risk of a community acquired pneumonia,

wherein the community acquired pneumonia is due to Streptococcuspneumoniae (penicillin susceptible and resistant isolates) includingcases with concurrent bacteremia, Haemophilus influenzae (includingbeta-lactamase positive isolates), Moraxella catarrhalis, or atypicalbacteria like Mycoplasma spp.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a complicated urinary tractinfection in a human or animal comprising administering to the human oranimal an effective amount of a compound according to formula I, II,III, IV, V, VI, VII, or VIII, or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof, or to the use of a compoundaccording to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,in the manufacture of a medicament for treating, preventing, or reducingthe risk of a complicated urinary tract infection

wherein the complicated urinary tract infection is selected frompyelonephritis due to Escherichia coli, concurrent bacteremia, orKlebsiella pneumoniae.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of an acute pelvic infectionin a human or animal comprising administering to the human or animal aneffective amount of a compound according to formula I, II, III, IV, V,VI, VII, or VIII, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, or to the use of a compound according toformula I, U, III, IV, V, VI, VII, or VIII, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof, in the manufactureof a medicament for treating, preventing, or reducing the risk of anacute pelvic infection

wherein the acute pelvic infection including postpartum endomyometritis,septic abortion and post surgical gynecologic infections is due toStreptococcus agalactiae, Escherichia coli, Bacteroides fragilis,Porphyromonas asaccharolytica, Peptostreptococcus spp., or Prevotellabivia.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a hospital acquiredpneumonia/ventilator associated pneumonia in a human or animalcomprising administering to the human or animal an effective amount of acompound according to formula I, II, III, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,or to the use of a compound according to formula I, II, III, IV, V, VI,VII, or VIII, or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof, in the manufacture of a medicament for treating,preventing, or reducing the risk of a hospital acquiredpneumonia/ventilator associated pneumonia,

wherein the hospital acquired pneumonia/ventilator associated pneumoniais due to Streptococcus pneumoniae (penicillin susceptible and resistantisolates), Staphylococcus aureus (methicillin susceptible and resistantisolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacterspp., Stenotrophomonas maltophilia, Haemophilus influenzae (includingbeta-lactamase positive isolates), or Legionella pneumophilia.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a microbial infectionassociated with an aerobic and facultative gram-positive microorganismin a human or animal comprising administering to the human or animal aneffective amount of a compound according to formula I, II, III, IV, V,VI, VII, or VIII, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, or to the use of a compound according toformula I, II, III, IV, V, VI, VII, or VIII, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof, in the manufactureof a medicament for treating, preventing, or reducing the risk of amicrobial infection associated with an aerobic and facultativegram-positive microorganism,

wherein the aerobic and facultative gram-positive microorganism isselected from: Staphylococcus aureus (methicillin susceptible andresistant isolates), Streptococcus pneumoniae (penicillin susceptibleand resistant isolates), Enterococcus spp. (vancomycin susceptible andresistant isolates), Streptococcus agalactiae, Streptococcus pyogenes,or Staphylococcus epidermidis (methicillin susceptible and resistantisolates).

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a microbial infectionassociated with an aerobic and facultative gram-negative microorganismin a human or animal comprising administering to the human or animal aneffective amount of a compound according to formula I, II, III, IV, V,VI, VII, or VIII, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, or to the use of a compound according toformula I, II, III, IV, V, VI, VII, or VIII, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof, in the manufactureof a medicament for treating, preventing, or reducing the risk of amicrobial infection associated with an aerobic and facultativegram-negative microorganism,

wherein the aerobic and facultative gram-negative microorganism isselected from: Escherichia coli (including ESBL and KPC producingisolates), Haemophilus influenzae (including Beta-lactamase positiveisolates), Klebsiella pneumoniae (including ESBL and KPC producingisolates), Citrobacter freundii, Enterobacter aerogenes, Enterobactercloacae, Morganella morganii, Serratia marcescens, Pseudomonasaeruginosa, Acinetobacter baumanni, Moraxella catarrhalis, Proteusmirabilis, Citrobacter koseri, Haemophilus parainfluenzae, Klebsiellaoxytoca (including ESBL and KPC producing isolates), Proteus vulgaris,Providencia reltgeri, or Providencia stuartii.

In some embodiments, the present invention relates to a method oftreating, preventing or reducing the risk of a microbial infectionassociated with an anaerobic microorganism in a human or animalcomprising administering to the human or animal an effective amount of acompound according to formula I, II, II, IV, V, VI, VII, or VIII, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,or to the use of a compound according to formula I, II, III, IV, V, VI,VII, or VIII, or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof, in the manufacture of a medicament for treating,preventing, or reducing the risk of a microbial infection associatedwith an anaerobic microorganism,

wherein the anaerobic microorganism is selected from: Bacteroidesfragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroidesthetaioaomicron, Bacteroides uniforms, Clostridium clostridioforme,Eubacterium lentum, Peptostreptococcus species, Porphyromonasasaccharolytica, Prevotella bivia, Bacteroides vulgates, Clostridiumperfringens, or Fusobacterium spp.

In some embodiments, the present invention relates to a method or usewherein the compound of the invention, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof, is administered otically,ophthalmically, nasally, orally, parenterally, topically, orintravenously.

In some embodiments, the present invention relates to a method ofsynthesizing a compound of the invention, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a medical devicecontaining a compound of the invention, or a pharmaceutically acceptablesalt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a medical devicecontaining a compound of the invention, wherein the device is a stent.

3. SYNTHESIS OF THE COMPOUNDS OF THE INVENTION

The invention provides methods for making the compounds of theinvention. The following Schemes 1c-2c depict exemplary routes ingeneral terms for synthesizing the compounds of the present invention.More specific chemical details are provided in the Examples.

4. CHARACTERIZATION OF COMPOUNDS OF THE INVENTION

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies.

A variety of binding assays can be useful in screening new molecules fortheir binding activity. One approach includes surface plasmon resonance(SPR) that can be used to evaluate the binding properties of moleculesof interest with respect to a ribosome, ribosomal subunit or a fragmentthereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor® fromPharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization.

Fluorescence polarization (FP) is a measurement technique that canreadily be applied to protein-protein, protein-ligand, or RNA-ligandinteractions in order to derive IC₅₀s and Kds of the associationreaction between two molecules. In this technique one of the moleculesof interest is conjugated with a fluorophore. This is generally thesmaller molecule in the system (in this case, the compound of interest).The sample mixture, containing both the ligand-probe conjugate and theribosome, ribosomal subunit or fragment thereof, is excited withvertically polarized light. Light is absorbed by the probe fluorophores,and re-emitted a short time later. The degree of polarization of theemitted light is measured. Polarization of the emitted light isdependent on several factors, but most importantly on viscosity of thesolution and on the apparent molecular weight of the fluorophore. Withproper controls, changes in the degree of polarization of the emittedlight depends only on changes in the apparent molecular weight of thefluorophore, which in-turn depends on whether the probe-ligand conjugateis free in solution, or is bound to a receptor. Binding assays based onFP have a number of important advantages, including the measurement ofIC₅₀s and Kds under true homogenous equilibrium conditions, speed ofanalysis and amenity to automation, and ability to screen in cloudysuspensions and colored solutions.

(3) Protein Synthesis.

It is contemplated that, in addition to characterization by theforegoing biochemical assays, the compound of interest can also becharacterized as a modulator (for example, an inhibitor of proteinsynthesis) of the functional activity of the ribosome or ribosomalsubunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is a inhibitor of protein synthesis.

(4) Antimicrobial Assays and Other Evaluations

Furthermore, the compounds can be assayed for anti-proliferative oranti-infective properties on a cellular level. For example, where thetarget organism is a microorganism, the activity of compounds ofinterest can be assayed by growing the microorganisms of interest inmedia either containing or lacking the compound. Growth inhibition canbe indicative that the molecule can be acting as a protein synthesisinhibitor. More specifically, the activity of the compounds of interestagainst bacterial pathogens can be demonstrated by the ability of thecompound to inhibit growth of defined strains of human pathogens. Forthis purpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms.

Minimum inhibitory concentrations (MICs) are determined by themicrodilution method, typically in a final volume of 100 microliters,according to protocols outlined by The Clinical and Laboratory StandardsInstitute [CLSI; formerly the National Committee for Clinical LaboratoryStandards (NCCLS)]. See CLSI: Methods for dilution antimicrobialsusceptibility tests for bacteria that grow aerobically; approvedstandard-fifth edition. Wayne, Pa.: NCCLS; 2000. The assays can be alsobe performed in microtiter trays according to conventional methodologiesas published by the CLSI. See CLSI. Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Seventh Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI,940 West Valley Road, Suite 1400, Wayne Pa. 19087-1898 USA, 2006).

The antimicrobial and other drug properties of the compounds can furtherbe evaluated in various in vivo mammalian assays, such as a mouse or ratperitonitis infectious models, skin and soft tissue models (oftenreferred to as the thigh model), or a mouse pneumonia model. There aresepticemia or organ infection models known to those skilled in the art.These efficacy models can be used as part of the evaluation process andcan be used as a guide of potential efficacy in humans. Endpoints canvary from reduction in bacterial burden to lethality. For the latterendpoint, results are often expressed as a PD₅₀ value, or the dose ofdrug that protects 50% of the animals from mortality.

To further assess a compound's drug-like properties, measurements ofinhibition of cytochrome P450 enzymes and phase II metabolizing enzymeactivity can also be measured either using recombinant human enzymesystems or more complex systems like human liver microsomes. Further,compounds can be assessed as substrates of these metabolic enzymeactivities as well. These activities are useful in determining thepotential of a compound to cause drug-drug interactions or generatemetabolites that retain or have no useful antimicrobial activity.

To get an estimate of the potential of the compound to be orallybioavailable, one can also perform solubility and Caco-2 assays. Thelatter is a cell line from human epithelium that allows measurement ofdrug uptake and passage through a Caco-2 cell monolayer often growingwithin wells of a 24-well microtiter plate equipped with a 1 micronmembrane. Free drug concentrations can be measured on the basolateralside of the monolayer, assessing the amount of drug that can passthrough the intestinal monolayer. Appropriate controls to ensuremonolayer integrity and tightness of gap junctions are needed. Usingthis same system one can get an estimate of P-glycoprotein mediatedefflux. P-glycoprotein is a pump that localizes to the apical membraneof cells, forming polarized monolayers. This pump can abrogate theactive or passive uptake across the Caco-2 cell membrane, resulting inless drug passing through the intestinal epithelial layer. These resultsare often done in conjunction with solubility measurements and both ofthese factors are known to contribute to oral bioavailability inmammals. Measurements of oral bioavailability in animals and ultimatelyin man using traditional pharmacokinetic experiments will determine theabsolute oral bioavailability.

Experimental results can also be used to build models that help predictphysical-chemical parameters that contribute to drug-like properties.When such a model is verified, experimental methodology can be reduced,with increased reliance on the model predictability.

5. FORMULATION AND ADMINISTRATION

The compounds of the invention can be useful in the prevention ortreatment of a variety of human or other animal, including mammalian andnon mammalian, disorders, including for example, bacterial infection,fungal infections, viral infections, diarrhea, parasitic diseases, andcancer. It is contemplated that, once identified, the active moleculesof the invention can be incorporated into any suitable carrier prior touse. The dose of active molecule, mode of administration and use ofsuitable carrier will depend upon the intended recipient and targetorganism. The formulations, both for veterinary and for human medicaluse, of compounds according to the present invention typically includesuch compounds in association with a pharmaceutically acceptablecarrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith the other ingredients of the formulations and not deleterious tothe recipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,anti-bacterial and anti-fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances isknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds (identified or designedaccording to the invention and/or known in the art) also can beincorporated into the compositions. The formulations can conveniently bepresented in dosage unit form and can be prepared by any of the methodswell known in the art of pharmacy/microbiology. In general, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to becompatible with its intended route of administration. Examples of routesof administration include oral, otic, ophthalmic, nasal, or parenteral,for example, intravenous, intradermal, inhalation, transdermal(topical), transmucosal, and rectal administration. Solutions orsuspensions used for parenteral, intradermal, or subcutaneousapplication can include the following components: a sterile diluent suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. pH can be adjusted with acids or bases,such as hydrochloric acid or sodium hydroxide.

Useful solutions for oral or parenteral administration can be preparedby any of the methods well known in the pharmaceutical art, described,for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.),Mack Pub., (1990). Formulations for parenteral administration can alsoinclude glycocholate for buccal administration, methoxysalicylate forrectal administration, or citric acid for vaginal administration. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Suppositories forrectal administration also can be prepared by mixing the drug with anon-irritating excipient such as cocoa butter, other glycerides, orother compositions which are solid at room temperature and liquid atbody temperatures. Formulations also can include, for example,polyalkylene glycols such as polyethylene glycol, oils of vegetableorigin, and hydrogenated naphthalenes. Formulations for directadministration can include glycerol and other compositions of highviscosity. Other potentially useful parenteral carriers for these drugsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes. Formulations for inhalationadministration can contain as excipients, for example, lactose, or canbe aqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or moulding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Moulded tablets can be madeby moulding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as manitol, sorbitol, orsodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Particularly usefulare carriers capable of forming a film or layer over the skin tolocalize application and inhibit removal. For topical administration tointernal tissue surfaces, the agent can be dispersed in a liquid tissueadhesive or other substance known to enhance adsorption to a tissuesurface. For example, hydroxypropylcellulose or fibrinogen/thrombinsolutions can be used to advantage. Alternatively, tissue-coatingsolutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants generally are known in the art, and include, forexample, for transmucosal administration, detergents and bile salts.Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, the activecompounds typically are formulated into ointments, salves, gels, orcreams as generally known in the art.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. Liposomalsuspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. Furthermore, administration can be by periodicinjections of a bolus, or can be made more continuous by intravenous,intramuscular or intraperitoneal administration from an externalreservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for otic, ophthalmic, nasal, parenteral or oraladministration to humans or other mammals, for example, intherapeutically effective amounts, e.g., amounts that provideappropriate concentrations of the drug to target tissue for a timesufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, e.g., by otic, ophthalmic, nasal, oral or parenteraladministration, using any of the methods and formulations describedherein and/or known in the art. Where the drug comprises part of atissue or organ preservation solution, any commercially availablepreservation solution can be used to advantage. For example, usefulsolutions known in the art include Collins solution, Wisconsin solution,Belzer solution, Eurocollins solution and lactated Ringer's solution.

The compounds of the present invention can be administered directly to atissue locus by applying the compound to a medical device that is placedin contact with the tissue. An example of a medical device is a stent,which contains or is coated with one or more of the compounds of thepresent invention.

For example, an active compound can be applied to a stent at the site ofvascular injury. Stents can be prepared by any of the methods well knownin the pharmaceutical art. See, e.g., Fattori, R. and Piva, T., “DrugEluting Stents in Vascular Intervention,” Lancet, 2003, 361, 247-249;Morice, M. C., “A New Era in the Treatment of Coronary Disease?”European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al.,“Sirolimus-Eluting Stents: A Review of Experimental and ClinicalFindings,” Z. Kardiol., 2002, 91(3), 49-57. The stent can be fabricatedfrom stainless steel or another bio-compatible metal, or it can be madeof a bio-compatible polymer. The active compound can be linked to thestent surface, embedded and released from polymer materials coated onthe stent, or surrounded by and released through a carrier which coatsor spans the stent. The stent can be used to administer single ormultiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods describedherein can be administered to individuals to treat disorders(prophylactically or therapeutically). In conjunction with suchtreatment, pharmacogenomics (i.e., the study of the relationship betweenan individual's genotype and that individual's response to a foreigncompound or drug) can be considered. Differences in metabolism oftherapeutics can lead to severe toxicity or therapeutic failure byaltering the relation between dose and blood concentration of thepharmacologically active drug. Thus, a physician or clinician canconsider applying knowledge obtained in relevant pharmacogenomicsstudies in determining whether to administer a drug as well as tailoringthe dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections inmammals, the compounds or pharmaceutical compositions thereof will beadministered otically, ophthalmically, nasally, orally, parenterallyand/or topically at a dosage to obtain and maintain a concentration,that is, an amount, or blood-level or tissue level of active componentin the animal undergoing treatment which will be anti-microbiallyeffective. Generally, an effective amount of dosage of active componentwill be in the range of from about 0.1 to about 100, more preferablyfrom about 1.0 to about 50 mg/kg of body weight/day. The amountadministered will also likely depend on such variables as the type andextent of disease or indication to be treated, the overall health statusof the particular patient, the relative biological efficacy of thecompound delivered, the formulation of the drug, the presence and typesof excipients in the formulation, and the route of administration. Also,it is to be understood that the initial dosage administered can beincreased beyond the above upper level in order to rapidly achieve thedesired blood-level or tissue level, or the initial dosage can besmaller than the optimum and the daily dosage can be progressivelyincreased during the course of treatment depending on the particularsituation. If desired, the daily dose can also be divided into multipledoses for administration, for example, two to four times per day.

Various disease states or conditions in humans and other mammals arefound to be caused by or mediated by nonsense or missense mutations.These mutations cause or mediate the disease state or condition byadversely affecting, for example, protein synthesis, folding,trafficking and/or function. Examples of disease states or conditions inwhich an appreciable percentage of the disease or condition is believedto result from nonsense or missense mutations include hemophilia (factorVIII gene), neurofibromatosis (NF1 and NF2 genes), retinitis pigmentosa(human USH2A gene), bullous skin diseases like Epidermolysis bullosapruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosistransmembrane regulator gene), breast and ovarian cancer (BRCA1 andBRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), coloncancer (mismatch repair genes, predominantly in MLH1 and MSH2), andlysosomal storage disorders such as Neimann-Pick disease (acidsphingomyelinase gene). See Sanders C R, Myers J K. Disease-relatedmisassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes anddisease Bethesda, Md.: NCBI, NLM ID: 101138560; and Raskó, István;Downes, C S Genes in medicine: molecular biology and human geneticdisorders 1st ed. London; New York: Chapman & Hall, 1995. NLM ID:9502404. The compounds of the present invention can be used to treat orprevent a disease state in a mammal caused or mediated by such nonsenseor missense mutations by administering to a mammal in need thereof aneffective amount of the present invention to suppress the nonsense ormissense mutation involved in the disease state.

6. EXAMPLES

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (E M Merck, Silica Gel 60,230-400 mesh) unless otherwise noted.

The compounds of the present invention can be prepared using knownchemical transformations adapted to the particular situation at hand.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below: h or hr=hour(s);min=minute(s); mol=mole(s); mmol=millimole(s); M=molar, μM=micromolar,g=gram(s); μg=microgram(s); rt=room temperature; L=liter(s);mL=milliliter(s); Et₂O=diethyl ether, THF=tetrahydrofuran; DMSO=dimethylsulfoxide; EtOAc=ethyl acetate; Et₃N=triethylamine; i-Pr₂NEt orDIPEA=diisopropylethylamine; CH₂Cl₂=methylene chloride;CHCl₃=chloroform; CDCl₃=deuterated chloroform; CCl₄=carbontetrachloride; MeOH=methanol; CD₃OD=deuterated methanol; EtOH=ethanol;DMF=dimethylformamide: BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;TBS=t-butyldimethylsilyl; TBSCl=t-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicycloundecene;TBDPSCl=t-butyldiphenylchlorosilane; Hunig'sBase=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; CuI=copper(l) iodide; MsCl=methanesulfonyl chloride; NaN₃=sodium azide;Na₂SO₄=sodium sulfate; NaHCO₃=sodium bicarbonate; NaOH=sodium hydroxide;MgSO₄=magnesium sulfate; K₂CO₃=potassium carbonate; KOH=potassiumhydroxide; NH₄OH=ammonium hydroxide; NH₄Cl=ammonium chloride;SiO₂=silica; Pd—C=palladium on carbon;Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II).

Exemplary compounds synthesized in accordance with the invention arelisted in Table 1. A bolded or dashed bond is shown to indicate aparticular stereochemistry at a chiral center, whereas a wavy bondindicates that the substituent can be in either orientation or that thecompound is a mixture thereof. It should also be known that in theinterest of conserving space, the chemical structures of some compoundshave been split into two parts with the two points of connection eachbeing indicated by a bond crossed by a wavy line. See, e.g. compound956, which was drawn in two parts as:

but corresponds to the complete chemical structure:

The compounds of the present invention can be prepared, formulated, anddelivered as salts, esters, and prodrugs. For convenience, the compoundsare generally shown without indicating a particular salt, ester, orprodrug form.

Compounds of the present invention are shown in Table 1. LCMS (liquidchromatography mass spectral) data are provided, where available. Whendata is not available this is indicated by “NA”. The LCMS data areprovided using the convention for m/z in the format, [M+H]⁺, exceptotherwise indicated.

TABLE 1 Comp. No. Structure LCMS  392

385.10  393

458.00  396

442.00  400

527.00  402

458.00  440

527.00  442

442.00  460

482.00  528

341.90  529

383.90  543

356.10  544

384.10  557

370.20  558

486.10  575

398.20  576

426.10  578

285.00  579

407.00  592

464.10  595

298.90  598

355.90  603

398.10  604

370.30  606

400.10  614

463.00  615

466.10  627

505.20  638

596.90  639

509.20  641

571.10  642

554.30  643

559.10  651

573.10  656

539.20  657

553.10  658

568.10  659

549.10  660

507.20  664

559.30  667

543.10  669

540.20  671

543.10  672

501.10  674

552.10  675

5871.10  676

499.10  681

611.20  685

557.10  686

494.10  689

553.10  690

529.20  691

552.40  694

571.10  695

 

580.20  696

567.10  707

535.20  708

552.30  714

482.20  715

566.30  718

554.30  729

654.40  730

638.30  731

525.10  732

567.30  733

604.20  738

608.30  740

509.10  741

553.10  748

691.30  749

733.40  750

625.30  751

566.30  752

580.30  753

747.40  754

705.40  763

535.10  765

618.20  774

581.00  776

564.30  777

592.30  781

568.30  782

640.20  783

592.30  792

 

580.30  793

538.40  794

 

594.30  795

510.30  798

511.30  811

 

552.30  812

 

618.30  818

575.10  832

538.60  833

523.40  858

415.20  859

 

552.30  868

 

706.30  869

 

747.50  870

482.40  888

482.40  889

499.20  890

468.10  891

425.10  903

482.30  904

 

581.10  908

425.10  909

425.20  916

 

538.30  917

 

538.30  919

386.20  920

455.10  921

455.20  929

347.90  938

479.30  941

 

566.30  942

 

538.30  950

524.00  953

 

539.30  954

 

498.20  955

 

498.30  956

 

511.40  972

382.00  973

 

648.50  976

 

648.60  993

481.80 1006

 

522.80 1007

 

536.70 1008

 

454.80 1014

 

602.60 1016

 

649.40 1025

 

621.40 1026

 

646.60 1030

 

624.40 1031

 

646.30 1032

495.20 1033

 

761.30 1041

580.40 1042

612.40 1055

 

633.40 1056

 

649.40 1058

 

647.40 1070

 

619.20 1071

 

651.30 1072

 

633.60 1073

 

647.40 1082

 

630.40 1083

 

643.00 1084

 

629.40 1086

453.20 1096

652.30 1133

531.20 1134

552.30 1135

594.40 1145

552.30 1146

510.30 1147

489.00 1192

522.10 1193

508.20 1197

504.10 1198

626.30 1212

491.10 1213

509.20 1234

507.50 1235

467.00 1236

509.20 1237

495.20 1238

453.10 1244

496.50 1269

452.80 1270

 

495.20 1271

 

495.60 1368

396.3 1369

396.2 1370

510.1 1421

414.1 1426

413.9 1427

371.9 1441

455.6 1449

386.3 1450

405.4 1464

 

485.0 1465

 

471.9 1466

 

570.4 1467

419.0  360

420.10  362

456.10  367

484.10  371

486.10  375

383.90  377

486.10  378

432.10  379

492.10  380

460.10  390

470.00  391

470.10  411

452.10  426

500.10  430

484.00  447

461.10  469

471.10  568

425.00  569

368.00  570

368.10 4000c

342.90 4001c

415.10 4002c

505.20 4003c

477.30 4004c

457.90 4005c

358.10 4006c

485.30 4007c

443.30 4008c

483.4

In further embodiments, the compounds of the present invention do notencompass a compound having the structure:

The compounds of the present invention can be made using syntheticchemical techniques well known to those of skill in the art.

Example 1—Synthesis of 592

The compounds of the present invention can be made using syntheticchemical techniques well known to those of skill in the art, includingthe schemes outlined herein. For illustrative purposes, the synthesis ofcompound 592 is described below.

4-Benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester(11.98 g, 58.4 mmol, 1 equiv) in THF (80 mL) at 23° C. was added asaturated solution of sodium bicarbonate (200 mL) followed by benzylchloroformate (9.19 mL, 64.2 mmol, 1.1 equiv). The reaction was stirredfor 55 min then partitioned between ethyl acetate (200 mL) and water(100 mL). The organic layer was separated, washed with saturated brinesolution (200 mL), dried (MgSO₄), filtered and concentrated to give 20.4g of tan solid. This material was used in the next step without furtherpurification.

Piperidin-4-yl-carbamic acid benzyl ester

To a solution of 4-benzyloxycarbonylamino-piperidine-1-carboxylic acidtert-butyl ester (20.4 g, crude from previous step) in dichloromethane(100 mL) at 23° C. was added trifluoroacetic acid (40 mL). Afterstirring for 45 min the reaction mixture was concentrated. The residuewas dissolved in water (100 mL) then basified to pH 11 via addition ofsolid potassium carbonate. The resulting solution was extracted withdichloromethane (2×150 mL). The organic extracts were extremely cloudy;they were dried (Na₂SO₄), filtered and concentrated. The residue wasdissolved/suspended in chloroform (70 mL) and the observed particulateswere removed via filtration through a glass frit. The solution wasconcentrated to give 15 g of brown oil. This material was used withoutpurification in the subsequent step.

(3-Bromo-propyl)-carbamic acid tert-butyl ester

To 3-bromopropylamine hydrobromide (12.8 g, 58.4 mmol, 1 equiv) indichloromethane (200 mL) at 23° C. was added triethylamine (10.2 mmol,73.6 mmol, 1.26 equiv) followed by di-tert-butyl dicarbonate (12.8 g,58.4 mmol, 1 equiv). After stirring for 1 h the reaction mixture waswashed successively with water (200 mL) then saturated brine solution(200 mL); then dried (MgSO₄), filtered and concentrated to give 13.9 gof the desired product as a clear oil. The material was used immediatelyin the next step.

[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-carbamic acidbenzyl ester

To a solution of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4mmol, crude product from Boc-deprotection step) in dimethylformamide (60mL) at 23° C. was added potassium carbonate (12.1 g, 87.6 mmol, 1.5equiv), potassium iodide (4.85 g, 29.2 mmol, 0.5 equiv) and(3-bromo-propyl)-carbamic acid tert-butyl ester (13.9 g, 58.4 mmol, 1equiv). The resulting mixture was warmed to 60° C. (oil bath). After 90min at 60° C. the reaction mixture was cooled to 23° C. then partitionedbetween ethyl acetate and water (100 mL each). The organic layer wasseparated, washed with saturated brine solution (150 mL), dried (MgSO₄),filtered and concentrated. The product was purified using an IscoCombiFlash automated chromatography system. The residue was loaded ontoa 330 g silica gel column as a solution in dichloromethane (25 mL) theneluted with 2 M ammonia in methanol in dichloromethane (0-12.5% 2 Mammonia in methanol linear gradient over 12 column volumes at a flowrate of 100 mL/min) to give 16.9 g (43.2 mmol, 74% over 3 steps) of thetitle compound as a clear oil.

[3-(4-Amino-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester

To a solution of[1-3-tert-butoxycarbonylamino-propyl)-piperidin-4-yl]-carbamic acidbenzyl ester (16.9 g, 43.2 mmol, 1 equiv) in ethanol (200 mL) at 23° C.was added palladium on carbon (2.25 g, 10 wt. %, wet, Degussa type). Thereaction vessel was placed under an atmosphere of hydrogen (balloon) andstirred for 14 h. At this time tlc analysis indicated the reaction wasincomplete, the mixture was filtered through a pad of Celite, washingwith ethanol (100 mL). The resulting solution was treated with freshpalladium catalyst (2.25 g), then placed under an atmosphere of hydrogen(balloon) at 50° C. After 7 h tlc analysis indicates completeconsumption of the starting material. The reaction mixture was cooled to23° C., and then filtered through Celite, washing with ethanol (200 mL).The filtrate was concentrated to give 11.1 g (43.2 mmol, 100%) of thedesired compound.

[3-(4-Ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester

To a solution of [3-(4-amino-piperidin-1-yl)-propyl]-carbamic acidtert-butyl ester (7.34 g, 28.6 mmol, 1 equiv) in dichloromethane at 0°C. (ice-water bath) was added triethylamine (5.97 mL, 42.9 mmol, 1.5equiv) followed by phenyl chloroformate (3.97 mL, 31.4 mmol, 1.1 equiv).The reaction mixture was stirred for 2.5 h at 0° C., then partitionedbetween dichloromethane (200 mL) and saturated aqueous sodiumbicarbonate solution (250 mL). The organic layer was separated. Theaqueous layer was re-extracted with dichloromethane (50 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentrated togive 10.5 g of the phenyl carbamate as a white semi-solid. The cruderesidue was dissolved in methanol (60 mL) then treated with aqueousammonium hydroxide solution (28% ammonia, 60 mL). After stirring for 15h at 23° C. the reaction mixture was concentrated. The residue wastreated with ethyl ether (300 mL) to give a precipitate. After standingat 23° C. for 2 h, the precipitate was collected via filtration througha medium porosity glass frit. The collect white solid was dried in vacuoto give 6.23 g (20.8 mmol, 73%) of the desired urea.

(4-Bromo-2-nitro-phenoxy)-acetic acid ethyl ester

To a solution of 4-bromo-2-nitro-phenol (3.28 g, 15.0 mmol, 1 equiv) indimethylformamide (40 mL) at 23° C. was added potassium carbonate (4.14g, 30 mmol, 2 equiv) followed by ethyl bromoacetate (1.84 mL, 16.6 mmol,1.1 equiv). The resulting mixture was warmed to 60° C. (oil bath) for 90min then cooled to 23° C. The reaction mixture was partitioned betweenethyl acetate:heptane (1:1) and water (100 mL each). The organic layerwas separated and washed successively with water, saturated brinesolution (100 mL each) then dried (MgSO₄), filtered and concentrated togive 4.50 g (11.5 mmol, 77%) of the product as a yellow oil.

[4-(3-Fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl ester

To a solution of (4-bromo-2-nitro-phenoxy)-acetic acid ethyl ester (2.95g, 9.70 mmol, 1 equiv) and 1-ethynyl-3-fluorobenzene (1.34 mL, 11.6mmol, 1.2 equiv) in dimethylformamide (15 mL) in a microwave reactorvessel was added triethylamine (4.05 mL, 29.1 mmol, 3 equiv), copperiodide (55 mg, 0.29 mmol, 0.03 equiv) andtrans-dichlorobis(tri-o-tolylphosphine) palladium(II) (152 mg, 0.19mmol, 0.02 equiv). The reaction was placed under an argon atmospherethen heated to 80° C. in a microwave reactor for 30 min. The reactionmixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0N aqueous hydrochloric acid (100 mL each). The organic layer wasseparated and washed successively with saturated aqueous sodiumbicarbonate, 1:1 saturated aqueous sodium bicarbonate:saturated aqueousammonium chloride, saturated brine solution (100 mL each) then dried(MgSO₄), filtered and concentrated. The product was purified using anIsco CombiFlash automated chromatography system. The residue was loadedonto a 120 g silica gel column as a solution in dichloromethane (5 mL)then eluted with ethyl acetate in heptane (0-40% ethyl acetate lineargradient over 16 column volumes at a flow rate of 85 mL/min) to give1.72 g (5.01 mmol, 52%) of the title compound as a brown oil.

6-[2-(3-Fluoro-phenyl]-ethyl)-4H-benzo[1,4]oxazin-3-one

To a solution of [4-(3-fluoro-phenylethynyl)-2-nitro-phenoxy]-aceticacid ethyl ester (1.72 g, 5.01 mmol, 1 equiv) in ethyl acetate (50 mL)was added palladium on carbon (500 mg, 10 wt. %, wet, Degussa type). Thereaction vessel was placed under an atmosphere of hydrogen (balloon) andstirred at 23° C. for 15 h. At this time LCMS analysis indicated thereaction contains a mixture of the desired benzoxazinone product (major)and uncyclized aniline (minor). The mixture was filtered through a padof Celite, washing with ethyl acetate (100 mL). The solution wasconcentrated, then re-dissolved in ethyl acetate (100 mL) and refluxedfor 2 h. LCMS analysis indicates no improvement in cyclized:uncyclizedratio. Para-toluenesulfonic acid hydrate (111 mg) was added andresulting solution was refluxed for a further 1 h. The solution wascooled to 23° C. then washed successively with water, 1.0 N aqueoushydrochloric acid, saturated aqueous brine (100 mL each), dried (MgSO₄),filtered and concentrated. The product was purified using an IscoCombiFlash automated chromatography system. The residue was loaded ontoa 80 g silica gel column as a solution in dichloromethane (5 mL) theneluted with methanol in dichloromethane (0-5% methanol linear gradientover 18 column volumes at a flow rate of 60 mL/min) to give 1.15 g (4.24mmol, 85%) of the title compound as a tan solid.

{3-Chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine

To a solution of dimethylformamide (0.82 mL, 10.6 mmol, 2.5 equiv) inchloroform (10 mL) at 0° C. was added phosphorus(V) oxychloride (0.78mL, 8.49 mmol, 2 equiv). After stirring 10 min at 0° C., the reactionvessel was warmed to 23° C. for 10 min then re-cooled to 0° C. Asolution of 6-[2-(3-fluoro-phenyl)-ethyl]-4H-benzo[1,4]oxazin-3-one inchloroform (7 mL) was added. After stirring a further 5 min at 0° C. thereaction was warmed to reflux (oil bath) for 4 h then cooled to 23° C.and partitioned between dichloromethane and water (100 mL each). Theaqueous layer was adjusted to pH 12 with 5 N aqueous sodium hydroxide,and then the organic layer was separated. The organic layer was washedwith brine (100 mL) and set aside. The original aqueous layer wasre-extracted with dichloromethane (100 mL). The two organic extractswere combined, dried (MgSO₄), filtered and concentrated. The product waspurified using an Isco CombiFlash automated chromatography system. Theresidue was loaded onto a 80 g silica gel column as a solution indichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40%ethyl acetate linear gradient over 16 column volumes at a flow rate of60 mL/min) to give 985 mg (2.86 mmol, 67%) of the title compound as anorange/brown oil.

{3-[4-(3-{2-Dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamicacid tert-butyl ester

To a solution of{3-chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine(500 mg, 1.45 mmol, 1 equiv) and[3-(4-ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (435mg, 1.45 mmol, 1 equiv) in dioxane (15 mL) was added palladium(II)acetate (3.2 mg, 0.0145 mmol, 0.01 equiv),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos, 17 mg, 0.029mmol, 0.02 equiv) and cesium carbonate (709 mg, 2.18 mmol, 1.5 equiv).The reaction mixture was sparged with argon then the reaction vesselsealed (screw cap) and placed in 100° C. oil bath. After 14 h at 100° C.the reaction was cooled to 23° C., and then partitioned between ethylacetate and water (100 mL each). The organic layer was separated andwashed with saturated brine solution (100 mL) then dried (MgSO₄),filtered and concentrated. The product was purified using an IscoCombiFlash automated chromatography system. The residue was loaded ontoan 80 g silica gel column as a solution in dichloromethane (5 mL) theneluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammoniain methanol linear gradient over 18 column volumes at a flow rate of 60mL/min) to give 313 mg (0.515 mmol, 36%) of the title compound as ayellow/brown solid.

[3-(4-{7-[2-(3-Fluoro-phenyl)-ethyl]-2-oxo-2,9-dihydro-1-oxa-1,3,9-triaza-anthracen-3-yl}-piperidin-1-yl)-propyl]-carbamicacid tert-butyl ester

A solution of{3-[4-(3-{2-dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamicacid tert-butyl ester (310 mg, 0.510 mmol, 1 equiv) in acetic acid (15mL) was placed in a microwave reactor vessel. The reaction was placedunder an argon atmosphere then heated to 100° C. in a microwave reactorfor 90 min. LCMS analysis indicated the desired product was obtained,but partial loss of Boc had occurred. The acetic acid solution wasconcentrated then the residue was dissolved in tetrahydrofuran (25 mL)and treated with potassium carbonate (600 mg, 4.34 mmol, 8.5 equiv) anddi-tert-butyl dicarbonate (190 mg, 0.872 mmol, 1.7 equiv). Afterstirring for 30 min at 23° C. the reaction mixture was partitionedbetween ethyl acetate and water (60 mL each). The organic layer wasseparated and washed with saturated brine solution (50 mL) then dried(MgSO₄), filtered and concentrated. The residue was dissolved/suspendedin 1:1 ethyl acetate:heptane (10 mL, hot). After cooling the solid wascollected via filtration. The solid was adsorbed onto silica gel (5 g)then purified using an Isco CombiFlash automated chromatography system.The product was eluted through and 40 g silica gel cartridge with 2 Mammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanollinear gradient over 24 column volumes at a flow rate of 40 mL/min) togive 94 mg (0.167 mmol, 33%) of the title compound as a pale yellowsolid.

3-[1-(3-Amino-propyl)-piperidin-4-yl]-7-[2-3-fluoro-phenyl)-ethyl]-3H,9H-10-oxa-1,3,9-triaza-anthracen-2-one

To a solution of[3-(4-{7-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,9-dihydro-10-oxa-1,3,9-triaza-anthracen-3-yl}-piperidin-1-yl)-propyl]-carbamicacid tert-butyl ester (94 mg, 0.167 mmol, 1 equiv) in dichloromethane(10 mL) at 23° C. was added trifluoroacetic acid (4.0 mL). The reactionwas stirred for 30 min then concentrated. The residue was dissolved inwater (10 mL) then treated with 1.0 N aqueous hydrochloric acid (2.0mL). The resulting solution was concentrated, and then the residue wasre-dissolved in water (10 mL), treated with hydrochloric acid (2.0 mL)and concentrated. The residue was dissolved in water (10 mL) and thenthe resulting solution was frozen and then lyophilized to give 88 mg(0.165 mmol, 99%) of the desired product (dihydrochloride salt) as ayellow solid. LCMS (EI): 464.1 (M+H)⁺.

3-Chloro-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (2)

4.05 mL of DMF (52.5 mmol, 2.5 equiv) was added to CHCl₃ (100 mL), downto 0 again and added 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (1) (4.36 g, 21 mmol, 1.0 equiv) at 0° C., and theresulting reaction mixture was heated up to reflux for 6 h. When TLC andLCMS showed the reaction was complete, the reaction mixture was cooledto RT and partitioned with dichloromethane and water, and aqueous layerwas basified with 5N of NaOH to pH 12 and extracted with dichloromethane(3×100 mL), the combined organic layer was concentrated and purified bycolumn chromatography (SiO₂, 20-50% EtOAc/Heptane gradient elution) toafford the desired3-Chloro-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (2) (4.13 g, 5.9 g, theoretical, 70%) as yellowsolids.

3-{3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-ureido}-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (4) and3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,3,9,9a-tetrahydro-1H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid methyl ester (5)

A solution of3-Chloro-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (2) (1.28 g, 4.6 mmol, 1.0 equiv) and[3-(4-Ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (3)(1.37 g, 4.6 mmol, 1.0 equiv) in dioxane (20.0 mL) was treated withPd(OAc)₂ (20.6 mg, 0.092 mmol, 0.02 equiv), Xantphos (10.6 mg, 0.18mmol, 0.04 equiv) and Cs₂CO₃ (2.25 g, 6.9 mmol, 1.5 equiv), and theresulting reaction mixture was heated to 90° C. for 6 h. When TLC and MSshowed the reaction was complete, the reaction mixture was directlyadded with Acetic acid (8 ml) stirred at 100° C. for 1 h withoutisolating3-{3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-ureido}-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (4) from the reaction mixture. The reaction solutionwas concentrated in vacuo, and the residue was directly purified bycolumn chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂ gradient elution) toafford the desired3-[1-(3-tert-Butoxycarbonylamino-propy)-piperidin-4-yl]-2-oxo-2,3,9,9a-tetrahydro-1H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid methyl ester (5)

(760 mg, 2295.4 mg theoretical, 33%) as a brown oily material. For 4:C₂₇H₄₀N₆O₆, LCMS (EI) m/e 545 (M⁺+H). For 5: C₂₅H₃₃N₅O₆, LCMS (EI) m/e500 (M⁺+H).

3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid (6)

1M of LiOH aqueous solution (4.5 mL, 3 equiv) and3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,3,9,9a-tetrahydro-1H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid methyl ester (5, 760 mg, 1.52 mmol, 1.0 equiv) was added to THF (5mL), warmed up to 50° C. and stirred until LCMS showed no startingmaterial left. The reaction solution was cooled to RT and extracted withEtOAc. The aqueous layer was acidified to pH 2 and the desired productwas precipitated and filtered to yield3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid (412 mg, 738 mg theoretical, 56%) as a light brown solid. For 6:C₂₄H₃₁N₅O₆, LCMS (EI) m/e 486 (M⁺+H).

4-[3-({3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-exo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carbonyl}-amino)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (7)

A solution of3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid (6) (150 mg, 0.31 mmol, 1 equiv) and4-(3-Amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (150mg, 0.62 mmol, 2.0 equiv) in DMF (S mL) was treated with HATU (235 mg,0.62 mmol, 2.0 equiv) and Hunig's base. The resulting solution wasstirred at RT for 6 h. When TLC and LCMS showed the reaction wascomplete, the reaction solution was concentrated in vacuo, and theresidue was directly purified by column chromatography (SiO₂, 0-10%MeOH/CH₂Cl₂ gradient elution) to afford the desired4-[3-({3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro3H-10-oxa-1,3,9-triaza-anthracene-7-carbonyl}-amino)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (106 mg, 220 mg, theoretical, 48%), which wastreated with 4M HCl in dioxane to afford the final product3-[1-(3-Amino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylicacid (3-piperazin-1-yl-propyl)-amide (8). For 7: C₃₆H₅₄N₈O₇, LCMS (EI)m/e 711 (M⁺+H). For 8: C₂₆H₃₈N₈O₃, LCMS (EI) m/e 511 (M⁺+H).

Example 2—Antimicrobial Activity

The compounds of the present invention were tested for antimicrobialactivity. These data are presented in Table 2. The compounds were runagainst Escherichia coli strain ATCC25922 using a standard microdilutionassay to determine minimum inhibitory concentrations (MICs). The data ispresented whereby a “+” indicates that the compound has an MIC value of16 micrograms/ml or less and a “−” indicates that the compound has anMIC value greater than 16 micrograms/ml. A “N/A” means that data isunavailable. It will be recognized by one skilled in the art that thecompounds can be assessed against other bacterial organisms and that thepresentation of data for activity against Escherichia coli isillustrative and in no way is intended to limit the scope of the presentinvention. The compounds of the present invention can be assayed againsta range of other microorganisms depending upon the performance activitydesired to be gathered. Furthermore, the “+”, “−”, and “N/A”representation and the selection of a cutoff value of 16 micrograms/mlis also illustrative and in no way is intended to limit the scope of thepresent invention. For example, a “−” is not meant to indicate that thecompound necessarily lacks activity or utility, but rather that its MICvalue against the indicated microorganism is greater than 16micrograms/ml.

TABLE 2 Compound E. coli Number ATCC25922 MIC  392 −  393 −  396 −  400−  402 −  440 −  442 −  460 −  528 −  529 −  543 −  544 −  557 −  558 − 575 −  576 −  578 −  579 −  592 +  595 −  598 −  603 +  604 −  606 − 614 −  615 −  627 +  638 −  639 −  641 −  642 −  643 −  651 −  656 − 657 −  658 −  659 −  660 −  664 −  667 −  669 −  671 −  672 −  674 − 675 −  676 −  681 −  685 −  686 −  689 +  690 −  691 −  694 −  695 + 696 +  707 +  708 +  714 −  715 +  718 −  729 +  730 −  731 +  732 + 733 −  738 −  740 +  741 +  748 −  749 +  750 −  751 +  752 +  753 + 754 +  763 −  765 +  774 +  776 +  777 +  781 +  782 −  783 +  792 + 793 +  794 +  795 −  798 −  811 +  812 −  818 +  832 +  833 +  858 − 859 +  868 +  869 +  870 −  888 −  889 −  890 −  891 −  903 −  904 + 908 −  909 −  916 −  917 +  919 +  920 −  921 −  929 −  938 +  941 + 942 +  950 +  953 +  954 +  955 +  956 +  972 −  973 −  976 −  993 +1006 − 1007 − 1008 − 1014 − 1016 − 1025 − 1026 − 1030 − 1031 − 1032 +1033 + 1041 − 1042 − 1055 − 1056 − 1058 − 1070 − 1071 − 1072 − 1073 −1082 − 1083 − 1084 − 1086 + 1096 − 1133 + 1134 + 1135 + 1145 + 1146 +1147 − 1192 − 1193 − 1197 − 1198 − 1212 − 1213 − 1234 + 1235 + 1236 +1237 + 1238 + 1244 + 1269 + 1270 + 1271 + 1368 − 1369 − 1370 + 1421 −1426 − 1427 − 1441 − 1449 − 1450 − 1464 − 1465 + 1466 + 1467 −  360 − 362 −  367 −  371 −  375 −  377 −  378 −  379 −  380 −  390 −  391 − 411 −  426 −  430 −  447 −  469 −  568 −  569 −  570 − 4000c − 4001c −4002c − 4003c − 4004c + 4005c − 4006c + 4007c − 4008c −

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A compound having the formula:

wherein -G-H-J, alternatively, is selected from

wherein each H and J is independently selected, or -G-H-J is selectedfrom:

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b) wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle; J is selected from NH₂,NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃, NHC(═O)NH₂, NHC(═NH)NH₂,NHC(═NH)H; wherein n is 0, 1, or 2; alternatively, -G-H-J is selectedfrom

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isa C or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3; J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈alkyl)₂, NHC(═O)CH₃, NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H; C-B-A-, -D-E-F,and -G-H-J are chemical moieties, wherein A, D and G are independentlyselected from the group consisting of: (a) a single bond, (b) —(C₁₋₈alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d) —(C₂₋₈ alkynyl)-, wherein i) 0-4carbon atoms in any of (b)-(d) immediately above optionally is replacedby a moiety selected from the group consisting of —O—, —S(O)_(p)—,—NR⁶—, —(C═O)—, —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—, ii)any of (b)-(d) immediately above optionally is substituted with one ormore R⁵ groups, and iii) any of (b)-(d) immediately above optionally issubstituted with —(C₁₋₈ alkyl)-R⁵ groups; (e) —O—, (f) —NR⁶—, (g)—S(O)_(p)—, (h) —C(O)—, (i) —C(O)O—, (j) —OC(O)—, k) —OC(O)O—, (l)—C(O)NR⁶—, (m) —NR⁶CO—, (n) —NR⁶C(O)NR⁶—, (o) —C(═NR⁶)—, (p) —C(═NR⁶)O—,(q) —OC(═NR⁶)—, (r) —C(═NR⁶)NR⁶—, (s) —NR⁶C(═NR⁶)—, (t) —C(═S)—, (u)—C(═S)NR⁶—, (v) —NR⁶C(═S)—, (w) —C(O)S—, (x) —SC(O)—, (y) —OC(═S)—, (z)—C(═S)O—, (aa) —NR⁶(CNR⁶)NR⁶—, (bb) —CR⁶R⁶C(O)—, (cc)—C(O)NR⁶(CR⁶R⁶)_(t)—, (dd) a 3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (ee) a 3-14 membersaturated, unsaturated, or aromatic carbocycle, and (ff) —(CR⁶R⁶)_(t)—,wherein (dd) or (ee) is optionally substituted with one or more R⁵groups; B, E, and H are independently selected from the group consistingof: (a) a single bond, (b) a 3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (c) a 3-14 membersaturated, unsaturated, or aromatic carbocycle, wherein (b) or (c) isoptionally substituted with one or more R⁵ groups; (d) —(C₁₋₈ alkyl)-,(e) —(C₂₋₈ alkenyl)-, (f) —(C₂₋₈ alkynyl)-, wherein i) 0-4 carbon atomsin any of (d)-(f) immediately above optionally is replaced by a moietyselected from the group consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—,—C(═NR⁶)—, —S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—, ii) anyof (d)-(f) immediately above optionally is substituted with one or moreR⁵ groups, and iii) any of (d)-(f) immediately above optionally issubstituted with —(C₁₋₈ alkyl)-R⁵ groups; and (g) —(CR⁶R⁶)_(t)—, C, F,and J are independently selected from the group consisting of: (a)hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h) —CN, (i) —N₃ (j)—NO₂, (k) —NR⁶(CR⁶R⁶)_(t)R⁸, (l) —OR⁸, (m) —S(O)_(p)(CR⁶R⁶)_(t)R⁸, (n)—C(O)(CR⁶R⁶)_(t)R⁸, (o) —OC(O)(CR⁶R⁶)_(t)R⁸, (p) —SC(O)(CR⁶R⁶)_(t)R⁸,(q) —C(O)O(CR⁶R⁶)_(t)R⁸, (r) —NR⁶C(O)(CR⁶R⁶)_(t)R⁸, (s)—C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (t) —C(═NR⁶)(CR⁶R⁶)_(t)R⁸, (u)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁸, (v) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁸, (w)—C(═NOR⁸)(CR⁶R⁶)_(t)R⁸, (x) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁸, (y)—OC(O)NR⁶(CR⁶R⁶)_(t)R⁸, (z) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁸, (aa)—NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁸, (bb) —S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁸, (cc)—NR⁶S(O)NR⁶(CR⁶R⁶)_(t)R⁸, (dd) —NR⁶R⁸, (ee) —NR⁶(CR⁶R⁶)R⁸, (f) —OH, (gg)—NR⁸R⁸, (hh) —OCH₃, (ii) —S(O)_(p)R⁸, (jj) —NC(O)R⁸, (kk)—NR⁶C(NR⁶)NR⁶R⁸, (ll) a C₁₋₈ alkyl group, (mm) a C₂₋₈ alkenyl group,(nn) a C₂₋₈alkynyl group, (oo) a 3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, (pp) a 3-14 membersaturated, unsaturated, or aromatic carbocycle, (qq)—(CR⁶R⁶)_(t)NR⁶(CR⁶R⁶)_(t)R⁸, (rr) —N[(CR⁶R⁶)_(t)R⁸][C═O(CR⁶R⁶)_(t)R⁸],(ss) —(CR⁶R⁶)_(t)N[(CR⁶R⁶)_(t)R⁸][(CR⁶R⁶)_(t)R⁸], (tt)—(CR⁶R⁶)_(t)NR⁶(C═O)(CR⁶R⁶)_(t)R⁸, (uu) - haloalkyl, (vv)—C(O)(CR⁶)[(CR⁶R⁶)_(t)R⁸]R⁸, (ww) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (xx)—(CR⁶R⁶)_(t)C(O)O(CR⁶R⁶)_(t)R⁸, (yy) —NR⁶C(O)CR⁸R⁸R⁸, (zz)—N[(CR⁶R⁶)_(t)R⁸]C(O)R⁸, and (aaa) —S(O)_(p)NR⁸R⁸; wherein (ll) through(pp) is optionally substituted with one or more R⁷ groups; R⁵ isselected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF₃, (g)—CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁸, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m)—C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl, (p) —(C₁₋₈alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s) —SR⁶, (t)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and (u) -3-14 member saturated, unsaturated, oraromatic carbocycle; alternatively, two R⁵ groups are taken together toform a carbocycle; wherein (m) through (r) and (t) through (u) isoptionally substituted with one or more R⁸; R⁶ is selected from (a)hydrogen, (b) —C₁₋₈ alkyl or alternatively two R⁶ groups are takentogether to form a carbocycle, (c) -haloalkyl, (d) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and (e) -3-14 member saturated, unsaturated, or aromaticcarbocycle; wherein (b) through (e) is optionally substituted with oneor more R⁸; R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e)I, (f) —CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl,(s) —NR⁶R⁸, (t) —OR⁸, (u) —(CR⁶R⁶)_(t)NR⁶R⁸, (v) —CR⁶R⁸R⁸, (w) —SR⁶, (x)-3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or aromaticcarbocycle, (z) —(CR⁶R⁶)_(t)C(O)NR⁸R⁸, (aa) —S(O)_(p)R⁸, (bb)—NR⁶C(O)NR⁶R⁶, (cc) —NR⁶C(O)R⁶, and (dd) —C(═NR⁶)NR⁶R⁶; wherein (m)through (q) and (x) through (y) are optionally substituted with one ormore R⁹; R⁸ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I,(f) —CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R⁹, (k) —OR⁹, (l)—NR⁶(CNR⁶)NR⁶R⁶, (m) —C₁₋₈ alkyl, (n) —C₁₋₈ alkenyl, (o) —C₁₋₈ alkynyl,(p) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur), (q) —(C₁₋₈ alkyl)-(3-14member saturated, unsaturated, or aromatic carbocycle), (r) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, (s) -3-14 member saturated, unsaturated, or aromatic carbocycle,(t) -haloalkyl, (u) —C(O)(CR⁶R⁶)_(t)R⁹, (v) —SR⁶, (w)—OC(O)(CR⁶R⁶)_(t)R⁹, (x) —NR⁶C(O)NR⁶R⁹, (y) —NR⁶C(O)R⁹, (z)—NR⁶(CNR⁹)(NR⁶R⁶), (aa) —ONR⁶(CNR⁶)NR⁶R⁶, (bb) —C(═NR⁹)NR⁶R⁶, (cc)—S(O)_(p)R⁹, (dd) —(CR⁶R⁶)_(t)C(O)NR⁶R⁹, (ee) —(CR⁶R⁶)_(t)OR⁹, and (ff)—(CR⁶R⁶)_(t)NR⁶R⁹; wherein (m) through (s) is optionally substitutedwith one or more R⁹; R⁹ is selected from (a) hydrogen, (b) F, (c) Cl,(d) Br, (e) I, (f) —CF₃, (g) —CN, (h) —N₃ (i) —NO₂, (j) —NR⁶R¹⁰, (k)—OR⁶, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m) —C(O)(CR⁶R⁶)_(t)NR⁶R⁶, (n) —C₁₋₈ alkyl,(o) —C₁₋₈ alkenyl, (p) —C₁₋₈ alkynyl, (q) -3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, (r)-3-14 member saturated, unsaturated, or aromatic carbocycle, (s)-haloalkyl, (t) —(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R¹⁰, (v) —C(O)R⁶,(w) —SR⁶, (x) —C(O)OR¹⁰, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur), (aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, oraromatic carbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd)—ONR⁶R⁶, (ee) —NR⁶C(O)NR⁶R⁶, (ff) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and(hh) —(CR⁶R⁶)_(t)NR⁶R¹⁰; wherein (n) through (r) and (z) through (aa) isoptionally substituted with one or more R¹⁰; R¹⁰ is selected from (a)hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF₃, (g) —CN, (h) —N₃ (i)—NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l) —NR⁶(CNR⁶)NR⁶R⁶, (m)—C(O)(CR⁶R⁶)_(t)NR⁶R⁶, (n) —C₁₋₈ alkyl, (o) —C₁₋₈ alkenyl, (p) —C₁₋₈alkynyl, (q) -3-14 member saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, (r) -3-14 member saturated,unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t)—(CR⁶R⁶)_(t)OR⁶, (u) —O(CR⁶R⁶)_(t)NR⁶R⁶, (v) —C(O)R⁶, (w) —SR⁶, (x)—C(O)OR⁶, (y) —S(O)_(p)R⁶, (z) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur),(aa) —(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (bb) —O(CR⁶R⁶)_(t)OR⁶, (cc) —C(═NR⁶)NR⁶R⁶, (dd) —ONR⁶R⁶,(ee) —NR⁶C(O)NR⁶R⁶, (ff) —O(CR⁶R⁶)_(t)OR⁶, (gg) —NR⁶C(O)R⁶, and (hh)—(CR⁶R⁶)_(t)NR⁶R⁶; optionally, wherein either the group -D-E-F or thegroup -G-H-J is absent, but both -D-E-F and -G-H-J are notsimultaneously absent; p is 0, 1, or 2, and t is 0, 1, 2, or 3, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.2. The compound according to claim 1, wherein A is selected from (a) a3-14 member saturated, unsaturated, or aromatic heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, (b) a 3-14 member saturated, unsaturated, oraromatic carbocycle, and (c) a single bond, wherein (a) or (b) isoptionally substituted with one or more R⁸ groups; B is selected from(a) —(C₁₋₈ alkyl)-, (b) —(C₂₋₈ alkenyl)-, (c) —(C₂₋₈ alkynyl)-, and (d)a single bond, wherein i) 0-4 carbon atoms in any of (a)-(c) immediatelyabove optionally is replaced by a moiety selected from the groupconsisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—, —S(O)_(p)NR⁶—,and —NR⁶S(O)_(p)NR⁶—, ii) any of (a)-(c) immediately above optionally issubstituted with one or more R⁵ groups, and iii) any of (a)-(c)immediately above optionally is substituted with —(C₁₋₈ alkyl)-R⁵groups, and C is selected from (a) NH₂, (b) —NHC(═NH)NH₂ and (c)hydrogen, or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof.
 3. The compound according to claim 2, wherein A isselected from azepanyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, phenyl, pyridinyl, cyclohexenyl, cyclohexadienyl,dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl,azetidinyl, pyrrolidinyl, piperidinyl and piperidenyl; wherein any of Aimmediately above optionally is substituted with one or more R⁵ groups;alternatively, A is a single bond; B is selected from (a) —(C₁₋₈alkyl)-, wherein i) 0-4 carbon atoms in (a) immediately above optionallyis replaced by a moiety selected from the group consisting of —O—,—S(O)_(p)—, —NR⁶—, —(C═O)—, —S(O)_(p)NR⁶—, and —NR⁶S(O)_(p)NR⁶—, ii) (a)immediately above optionally is substituted with one or more R⁵ groups,and iii) (a) immediately above optionally is substituted with —(C₁₋₈alkyl)-R⁵ groups; and alternatively, B is a single bond; C is selectedfrom (a) NH₂, (b) —NHC(═NH)NH₂ and (c) hydrogen; or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.
 4. The compoundaccording to claim 3, wherein C-B-A- is selected from the groupconsisting of: hydrogen,

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.
 5. The compound according to claim 1, wherein G is selectedfrom (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈ alkenyl)-, (d)—(C₂₋₈ alkynyl)-, wherein i) 0-4 carbon atoms in any of (b)-(d)immediately above optionally is replaced by a moiety selected from thegroup consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,—S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—, ii) any of (b)-(d)immediately above optionally is substituted with one or more R⁵ groups,and iii) any of (b)-(d) immediately above optionally is substituted with—(C₁₋₈ alkyl)-R⁵ groups; (e) a 3-14 member saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, and (f) a 3-14member saturated, unsaturated, or aromatic carbocycle, wherein (e) or(f) is optionally substituted with one or more R⁵ groups; or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.6. The compound according to claim 1, wherein R⁵ is selected from (a)hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF₃, (g) —CN, (h) —N₃ (i)—NO₂, (j) —NH₂, (k) —OR⁶, (l) —NHC(═NH)NH₂, (m) —C₁₋₈ alkyl, (n) —C₁₋₈alkenyl, (o) —C₁₋₈ alkynyl, (p) —(C₁₋₈ alkyl)-(3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur), (q)—(C₁₋₈ alkyl)-(3-14 member saturated, unsaturated, or aromaticcarbocycle), (r) -haloalkyl, (s) —SR⁶, (t) -3-14 member saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, and(u) -3-14 member saturated, unsaturated, or aromatic carbocycle;alternatively, two R⁵ groups are taken together to form a carbocycle; ora pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.7. The compound according to claim 1, wherein R⁶ is selected from (a)hydrogen, (b) —C₁₋₈ alkyl or alternatively two R⁶ groups are takentogether to form a carbocycle, (c) -haloalkyl, (d) -3-14 membersaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and (e) -3-14 member saturated, unsaturated, or aromaticcarbocycle; or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof.
 8. The compound according to claim 5, wherein Gselected from (a) a single bond, (b) —(C₁₋₈ alkyl)-, (c) —(C₂₋₈alkenyl)-, (d) —(C₂₋₈ alkynyl)-, wherein i) 0-4 carbon atoms in any of(b)-(d) immediately above optionally is replaced by a moiety selectedfrom the group consisting of —O—, —S(O)_(p)—, —NR⁶—, —(C═O)—, —C(═NR⁶)—,—S(O)_(p)NR⁶—, —NR⁶S(O)_(p)—, and —NR⁶S(O)_(p)NR⁶—, ii) any of (b)-(d)immediately above optionally is substituted with one or more R⁵ groups,and iii) any of (b)-(d) immediately above optionally is substituted with—(C₁₋₈ alkyl)-R⁵ groups; wherein p is 0, 1, or 2, or a pharmaceuticallyacceptable salt, ester, tautomer, or prodrug thereof.
 9. The compoundaccording to claim 1, wherein

is selected from:

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.
 10. The compound according to claim 9, wherein

is selected from:

or -G-H-J is selected from

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(y)and R_(z) are C or CH each independently substituted with one or more F,CH₃, CF₃, OH, and OCH₃; or R_(x), R_(y), and R_(z) are eachindependently selected from CH₂ or CR^(a)R^(b) wherein R^(a) and R^(b)are taken together to form a C₁₋₅ carbocycle; J is selected from NH₂,NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl)₂, NHC(═O)CH₃, NHC(═O)NH₂, NHC(═NH)NH₂,NHC(═NH)H; wherein n is 0, 1, or 2; alternatively, -G-H-J is selectedfrom

wherein R_(x) is selected from CH₂, NH, N(C₁₋₈ alkyl), S, or O; R_(z) isa C or CH, substituted with one or more CH₃ or R_(z) is CR^(a)R^(b)wherein R^(a) and R^(b) are taken together to form a C₁₋₅ carbocycle,wherein m is 1, 2, or 3; J is selected from NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈alkyl)₂, NHC(═O)CH₃, NHC(═O)NH₂, NHC(═NH)NH₂, NHC(═NH)H; or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.11. The compound according to claim 1, wherein the compound is one thatbinds to a ribosome.
 12. The compound according to claim 11, wherein theribosome is a bacterial ribosome.
 13. The compound according to claim 1,wherein the compound is selected from the group consisting of: Comp. No.Structure 360

362

367

371

375

377

378

379

380

390

391

411

426

430

447

469

or a pharmaceutically acceptable salt, ester, tautomer, or prodrugthereof.
 14. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, and a pharmaceutically acceptable carrier.15. A method for treating or reducing the risk of a disease state in ahuman or animal comprising administering to a human or animal in needthereof an effective amount of a compound according to claim 1, or apharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.16. A method of treating a microbial infection in a human or animalcomprising administering to the human or animal an effective amount of acompound according to claim 1, or a pharmaceutically acceptable salt,ester, tautomer, or prodrug thereof.
 17. A method of treating orreducing the risk of a microbial infection in a human or animalcomprising administering to the human or animal an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, ester,tautomer, or prodrug thereof, wherein the microbial infection isselected from the group consisting of: a skin infection, a Gram positiveinfection, a Gram negative infection, nosocomial pneumonia, communityacquired pneumonia, post-viral pneumonia, hospital acquiredpneumonia/ventilator associated pneumonia, a respiratory tract infectionsuch as CRTI (chronic respiratory tract infection), acute pelvicinfection, a complicated skin and skin structure infection, a skin andsoft tissue infection (SSTI) including uncomplicated skin and softtissue infections (uSSTI)s and complicated skin and soft tissueinfections, an abdominal infection, a complicated intra-abdominalinfection, a urinary tract infection, bacteremia, septicemia,endocarditis, an atrio-ventricular shunt infection, a vascular accessinfection, meningitis, surgical prophylaxis, a peritoneal infection, abone infection, a joint infection, a methicillin-resistantStaphylococcus aureus infection, a vancomycin-resistant Enterococciinfection, a linezolid-resistant organism infection, a Bacillusanthracis infection, a Francisella tularensis infection, a Yersiniapestis infection, and tuberculosis.
 18. The method of claim 15, whereinthe compound, or a pharmaceutically acceptable salt, ester, tautomer, orprodrug thereof, is administered otically, ophthalmically, nasally,orally, parenterally, intravenously, or topically.